Gene Summary

Gene:AIDA; axin interactor, dorsalization associated
Aliases: C1orf80
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:axin interactor, dorsalization-associated protein
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (7)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Immunohistochemistry
  • Follow-Up Studies
  • Chromosomal Instability
  • fms-Like Tyrosine Kinase 3
  • Adenocarcinoma
  • Idarubicin
  • Ovarian Cancer
  • Polymerase Chain Reaction
  • Oral Cavity Cancer
  • Cancer RNA
  • Biomarkers, Tumor
  • Chromosome 1
  • Molecular Sequence Data
  • Adolescents
  • In Situ Hybridization
  • Point Mutation
  • Survival Rate
  • Childhood Cancer
  • Oncogene Proteins
  • Microsatellite Instability
  • Base Sequence
  • Prostate Cancer
  • Mutation
  • Androgen Receptors
  • Cancer Gene Expression Regulation
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • FISH
  • Squamous Cell Carcinoma
  • Japan
  • Infant
  • Retinoic Acid
  • Leukemia, Promyelocytic, Acute
  • Neoplasm Proteins
  • Trisomy
  • Lung Cancer
  • Oncogene Fusion Proteins
  • Cancer DNA
  • Remission Induction
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: AIDA (cancer-related)

Vitkeviciene A, Baksiene S, Borutinskaite V, Navakauskiene R
Epigallocatechin-3-gallate and BIX-01294 have different impact on epigenetics and senescence modulation in acute and chronic myeloid leukemia cells.
Eur J Pharmacol. 2018; 838:32-40 [PubMed] Related Publications
Myeloid leukemia treatment is quite successful nowadays; nevertheless the development of new therapies is still necessary. In the present study, we investigated the potential of epigenetic modulators EGCG (epigallocatechin-3-gallate) and BIX-01294 (N-(1-benzylpiperidin-4-yl)-6,7-dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-amine) to alter epigenetic state and cause cellular senescence in acute and chronic myeloid leukemia NB4 and K562 cells. We have shown that after leukemia cell treatment with EGCG and BIX-01294 the proliferation and survival were inhibited of both cell lines; however, only NB4 cells underwent apoptosis. Both epigenetic modulators caused cell cycle arrest in G0/G1 phase as assessed by RT-qPCR (p53, p21, Rb) and flow cytometry analysis. Increased levels of ATM, HMGA2, phosphorylated ATM, and SA-β-galactosidase staining indicated that EGCG caused cellular senescence, whereas BIX-01294 did not. Immunoblot analysis of epigenetic players DNMT1, HP1α, H3K9me3, EZH2, and SUZ12 demonstrated beneficial epigenetic modulation by both agents with exception of mainly no epigenetic changes caused in K562 cells by EGCG. Therefore, we suggest EGCG as a promising epigenetic modulator for acute promyelocytic leukemia therapy and as a potential cellular senescence inducer in both acute and chronic myeloid leukemia treatment, whereas BIX-01294 could be beneficial as an epigenetic modifier for both myeloid leukemias treatment.

Yoshimura H, Matsuda Y, Yamamoto M, et al.
Reduced expression of the H19 long non-coding RNA inhibits pancreatic cancer metastasis.
Lab Invest. 2018; 98(6):814-824 [PubMed] Related Publications
H19 is an oncofetal RNA expressed in the developing embryo as well as in bladder, breast, gastric, pancreatic, hepatocellular, and prostate cancers. Recent studies have shown that H19 enhances cancer invasion and metastasis; however, its roles in cancer remain controversial. In the current study, H19 exhibited the second largest increase (82.4-fold) and represented the only non-protein coding gene among 11 genes identified that were elevated over 10-fold in lung-metastasis-derived pancreatic cancer cells compared with their parental cells using a mouse metastatic model. Subsequently, we further clarified the roles of H19 in pancreatic cancer growth and metastasis using in vitro and in vivo techniques. In situ hybridization showed that H19 was detected in 23 of 139 invasive ductal carcinomas (17%), and that H19 expression positively correlated with higher histological grades (P < 0.0001). Overexpression of H19 in PANC-1 pancreatic cancer cells induced higher motilities, whereas H19 inhibition using shRNA and siRNA showed opposite results; however, cell growth rates were not impacted. Intravenous injection of H19 shRNA vector-transfected PANC-1 cells yielded marked inhibition of metastasis in the liver and lungs of immunodeficient mice. These findings suggest that H19 has important roles in pancreatic cancer metastasis, and that inhibition of H19 represents a novel candidate for pancreatic cancer therapy.

Sasaki N, Ishiwata T, Hasegawa F, et al.
Stemness and anti-cancer drug resistance in ATP-binding cassette subfamily G member 2 highly expressed pancreatic cancer is induced in 3D culture conditions.
Cancer Sci. 2018; 109(4):1135-1146 [PubMed] Free Access to Full Article Related Publications
The expression of ATP-binding cassette subfamily G member 2 (ABCG2) is related to tumorigenic cancer stem cells (CSC) in several cancers. However, the effects of ABCG2 on CSC-related malignant characteristics in pancreatic ductal adenocarcinoma (PDAC) are not well elucidated. In this study, we compared the characteristics of low (ABCG2-) and high (ABCG2+)-ABCG2-expressing PDAC cells after cell sorting. In adherent culture condition, human PDAC cells, PANC-1, contained approximately 10% ABCG2+ cell populations, and ABCG2+ cells displayed more and longer microvilli compared with ABCG2- cells. Unexpectedly, ABCG2+ cells did not show significant drug resistance against fluorouracil, gemcitabine and vincristine, and ABCG2- cells exhibited higher sphere formation ability and stemness marker expression than those of ABCG2+ cells. Cell growth and motility was greater in ABCG2- cells compared with ABCG2+ cells. In contrast, epithelial-mesenchymal transition ability between ABCG2- and ABCG2+ cells was comparable. In 3D culture conditions, spheres derived from ABCG2- cells generated a large number of ABCG2+ cells, and the expression levels of stemness markers in these spheres were higher than spheres from ABCG2+ cells. Furthermore, spheres containing large populations of ABCG2+ cells exhibited high resistance against anti-cancer drugs presumably depending on ABCG2. ABCG2+ cells in PDAC in adherent culture are not correlated with stemness and malignant behaviors, but ABCG2+ cells derived from ABCG2- cells after sphere formation have stemness characteristics and anti-cancer drug resistance. These findings suggest that ABCG2- cells generate ABCG2+ cells and the malignant potential of ABCG2+ cells in PDAC varies depending on their environments.

Mizuno Y, Shimada S, Akiyama Y, et al.
DEPDC5 deficiency contributes to resistance to leucine starvation via p62 accumulation in hepatocellular carcinoma.
Sci Rep. 2018; 8(1):106 [PubMed] Free Access to Full Article Related Publications
Decrease in blood concentration of branched-chain amino acids, especially leucine, is known to promote liver carcinogenesis in patients with chronic liver disease, but the mechanism is unclear. We herein established hepatocellular carcinoma (HCC) cells knocked out for DEPDC5 by using the CRISPR/Cas9 system, and elucidated that cell viability of the DEPDC5 knockout (DEPDC5-KO) cells was higher than that of the DEPDC5 wild-type (DEPDC5-WT) under leucine starvation. Considering that autophagy deficiency might be involved in acquired resistance to leucine deprivation, we observed reduction of LC3-II followed by accumulation of p62 in the DEPDC5-KO, which induced reactive oxygen species (ROS) tolerance. DEPDC5 overexpression suppressed cell proliferation and tumorigenicity in immunocompromised mice, and triggered p62 degradation with increased ROS susceptibility. In clinical specimens of HCC patients, decreased expression of DEPDC5 was positively correlated with p62 overexpression, and the progression-free (PFS) and overall survival (OS) were worse in the DEPDC5-negative cases than in the DEPDC5-positive. Moreover, multivariate analysis demonstrated DEPDC5 was an independent prognostic factor for both PFS and OS. Thus, DEPDC5 inactivation enhanced ROS resistance in HCC under the leucine-depleted conditions of chronic liver disease, contributing to poor patient outcome. It could be a potential target for cancer therapy with oxidative stress control.

Aida S, Sonobe Y, Yuhki M, et al.
MITF suppression by CH5552074 inhibits cell growth in melanoma cells.
Cancer Chemother Pharmacol. 2017; 79(6):1187-1193 [PubMed] Related Publications
PURPOSE: Although treatment of melanoma with BRAF inhibitors and immune checkpoint inhibitors achieves a high response rate, a subset of melanoma patients with intrinsic and acquired resistance are insensitive to these therapeutics, so to improve melanoma therapy other target molecules need to be found. Here, we screened our chemical library to identify an anti-melanoma agent and examined its action mechanisms to show cell growth inhibition activity.
METHODS: We screened a chemical library against multiple skin cancer cell lines and conducted ingenuity pathway analysis (IPA) to investigate the mechanisms of CH5552074 activity. Suppression of microphthalmia-associated transcription factor (MITF) expression levels was determined in melanoma cells treated with CH5552074. Cell growth inhibition activity of CH5552074 was evaluated in MITF-dependent melanoma cell lines.
RESULTS: We identified an anti-melanoma compound, CH5552074, which showed remarkable cell growth inhibition activity in melanoma cell lines. The IPA results suggested that CH5552074-sensitive cell lines had activated MITF. In further in vitro studies in the melanoma cell lines, a knockdown of MITF with siRNA resulted in cell growth inhibition, which showed that CH5552074 inhibited cell growth by reducing the expression level of MITF protein.
CONCLUSIONS: These results suggest that CH5552074 can inhibit cell growth in melanoma cells by reducing the protein level of MITF. MITF inhibition by CH5552074 would be an attractive option for melanoma treatment.

Tsujimoto S, Yanagimachi M, Tanoshima R, et al.
Influence of ADORA2A gene polymorphism on leukoencephalopathy risk in MTX-treated pediatric patients affected by hematological malignancies.
Pediatr Blood Cancer. 2016; 63(11):1983-9 [PubMed] Related Publications
BACKGROUND: Methotrexate (MTX) can lead to neurotoxicity and asymptomatic leukoencephalopathy. However, the mechanism of MTX-related leukoencephalopathy is obscure. MTX and its metabolites inhibit 5-aminoimidazole-4-carboxamide ribonucleotide formiltransferase (ATIC) and promote adenosine release. Recently, it has been reported that adenosine and its receptor are related to certain central nervous system diseases. We investigated whether adenosine pathway gene polymorphisms and clinical factors were related to MTX-related leukoencephalopathy in pediatric patients affected by hematological malignancies.
PROCEDURE: Fifty-six Japanese childhood acute lymphoblastic leukemia or lymphoma patients were investigated. Patients were evaluated by magnetic resonance imaging of the brain before maintenance therapy or stem cell transplantation. Gene polymorphisms within the adenosine pathway (ATIC, adenosine A2A receptor [ADORA2A]) and the MTX pathway (methylenetetrahydrofolate reductase [MTHFR] and ABCB1) were genotyped using TaqMan assays. Clinical data were collected by accessing the medical records. MTX-related leukoencephalopathy was evaluated by a pediatric neurologist.
RESULTS: Twenty-one (37%) of 56 patients developed MTX-related leukoencephalopathy. Four of 21 patients developed clinical neurotoxicity. The minor allele CC genotype of rs2298383 (ADORA2A) was associated with MTX-related leukoencephalopathy (P = 0.010, odds ratio = 5.81, 95% confidence interval 1.50-22.50). High cumulative dose of systemic MTX was associated with MTX-related leukoencephalopathy after adjusting for sex, ADORA2A polymorphism, and prolonged high MTX concentration (P = 0.042, odds ratio = 1.18, 95% confidence interval 1.01-1.37).
CONCLUSIONS: ADORA2A rs2298383 and high cumulative dose of systemic MTX administration were significantly associated with MTX-related leukoencephalopathy. Our results indicate that pharmacological intervention within the adenosine pathway may be both a treatment and preventative option for MTX-related leukoencephalopathy.

Sasaki H, Yoshiike M, Nozawa S, et al.
Expression Level of Urinary MicroRNA-146a-5p Is Increased in Patients With Bladder Cancer and Decreased in Those After Transurethral Resection.
Clin Genitourin Cancer. 2016; 14(5):e493-e499 [PubMed] Related Publications
BACKGROUND: Bladder cancer is the most prevalent malignancy involving the urinary system and exhibits a markedly high recurrence rate. Therefore, reliable and noninvasive diagnostic and surveillance methods are desperately needed.
PATIENTS AND METHODS: Candidate microRNAs (miRNAs) were selected from the miRNAs that were differentially expressed in bladder cancer cell lines (T24 and RT4) compared to normal ureteral epithelial tissue using miRNA-microarray analysis. The candidate miRNAs were validated by quantitative reverse transcription polymerase chain reaction assay using voided urine samples.
RESULTS: We identified 3 miRNAs (miR-301b, -563, and -146a-5p) that demonstrated > 2-fold higher expression levels in cancer cell lines than in the normal ureteral epithelial tissue. Of these, only miR-146a-5p was consistently and significantly higher in urine samples from the patients with bladder cancer than in those from the normal individuals (P = .0014). The patients with high-grade tumors exhibited significantly higher urinary miR-146a-5p levels than those with low-grade tumors, and the patients with invasive tumors tended to show higher urinary miR-146a-5p levels than those with noninvasive tumors. Elevated urinary miR-146a-5p levels in patients with bladder cancer were decreased to the normal level after transurethral resection of the tumors (P = .0214).
CONCLUSION: Our study suggested that urinary miR-146a-5p might be useful as a new noninvasive diagnostic marker, therapeutic target, or anticancer agent for bladder cancer, as well as for increasing our understanding of cancer biology.

Yanagisawa M, Aida T, Takeda T, et al.
Arundic acid attenuates retinal ganglion cell death by increasing glutamate/aspartate transporter expression in a model of normal tension glaucoma.
Cell Death Dis. 2015; 6:e1693 [PubMed] Free Access to Full Article Related Publications
Glaucoma is the second leading cause of blindness worldwide and is characterized by gradual visual impairment owing to progressive loss of retinal ganglion cells (RGCs) and their axons. Glutamate excitotoxicity has been implicated as a mechanism of RGC death in glaucoma. Consistent with this claim, we previously reported that glutamate/aspartate transporter (GLAST)-deficient mice show optic nerve degeneration that is similar to that observed in glaucoma. Therefore, drugs that upregulate GLAST may be useful for neuroprotection in glaucoma. Although many compounds are known to increase the expression of another glial glutamate transporter, EAAT2/GLT1, few compounds are shown to increase GLAST expression. Arundic acid is a glial modulating agent that ameliorates delayed ischemic brain damage by attenuating increases in extracellular glutamate. We hypothesized that arundic acid neuroprotection involves upregulation of GLAST. To test this hypothesis, we examined the effect of arundic acid on GLAST expression and glutamate uptake. We found that arundic acid induces GLAST expression in vitro and in vivo. In addition, arundic acid treatment prevented RGC death by upregulating GLAST in heterozygous (GLAST(+/-)) mice. Furthermore, arundic acid stimulates the human GLAST ortholog, EAAT1, expression in human neuroglioblastoma cells. Thus, discovering compounds that can enhance EAAT1 expression and activity may be a novel strategy for therapeutic treatment of glaucoma.

Okamoto A, Sehouli J, Yanaihara N, et al.
Somatic copy number alterations associated with Japanese or endometriosis in ovarian clear cell adenocarcinoma.
PLoS One. 2015; 10(2):e0116977 [PubMed] Free Access to Full Article Related Publications
When compared with other epithelial ovarian cancers, the clinical characteristics of ovarian clear cell adenocarcinoma (CCC) include 1) a higher incidence among Japanese, 2) an association with endometriosis, 3) poor prognosis in advanced stages, and 4) a higher incidence of thrombosis as a complication. We used high resolution comparative genomic hybridization (CGH) to identify somatic copy number alterations (SCNAs) associated with each of these clinical characteristics of CCC. The Human Genome CGH 244A Oligo Microarray was used to examine 144 samples obtained from 120 Japanese, 15 Korean, and nine German patients with CCC. The entire 8q chromosome (minimum corrected p-value: q = 0.0001) and chromosome 20q13.2 including the ZNF217 locus (q = 0.0078) were amplified significantly more in Japanese than in Korean or German samples. This copy number amplification of the ZNF217 gene was confirmed by quantitative real-time polymerase chain reaction (Q-PCR). ZNF217 RNA levels were also higher in Japanese tumor samples than in non-Japanese samples (P = 0.027). Moreover, endometriosis was associated with amplification of EGFR gene (q = 0.047), which was again confirmed by Q-PCR and correlated with EGFR RNA expression. However, no SCNAs were significantly associated with prognosis or thrombosis. These results indicated that there may be an association between CCC and ZNF217 amplification among Japanese patients as well as between endometriosis and EGFR gene amplifications.

Ivanišević Malčić A, Breen L, Josić D, et al.
Proteomics profiling of keratocystic odontogenic tumours reveals AIDA as novel biomarker candidate.
J Oral Pathol Med. 2015; 44(5):367-77 [PubMed] Related Publications
BACKGROUND: Keratocystic odontogenic tumour (KCOT) is a benign, yet aggressive odontogenic tumour. Herein, proteome analysis of KCOT lesions in comparison with control patient-matched tissue unaffected by the disease and with inflammatory odontogenic cysts, namely radicular cysts is presented.
METHODS: For the proteomics profiling, two complementary proteomics techniques MALDI-MS/MS and LC-ESI-MS/MS were employed. Potential candidate biomarkers were validated by immunohistochemistry.
RESULTS: More than 43 proteins were found to be differentially expressed or up-regulated in KCOT lesions in comparison with patient-matched unaffected oral mucosa. These proteins bear important biological functions and are involved in cell proliferation, cytoskeletal re-organization, transcription, cellular motility and apoptosis. In particular, a number of differentially expressed proteins participate in autocrine regulation and signalization within JNK and p38 MAPK signalling pathways.
CONCLUSIONS: Immunohistochemical validation of chosen putative biomarkers revealed axin interaction partner and dorsalization-antagonist (AIDA), known as a protein that blocks activation of JNK signalling pathway, as a differential biomarker for KCOT lesions on an independent cohort of KCOT tissue samples in comparison with most prevalent intra-oseal lesions inflammatory odontogenic cysts.

Breccia M, De Propris MS, Stefanizzi C, et al.
Negative prognostic value of CD34 antigen also if expressed on a small population of acute promyelocytic leukemia cells.
Ann Hematol. 2014; 93(11):1819-23 [PubMed] Related Publications
Potential clinical significance of CD34 expression in acute promyelocitic leukemia (APL) has not been deeply investigated. We hereby analyzed the clinico-biological features and treatment outcome of APL patients in relation to CD34 expression, even when expressed in a small subpopulation: 114 APL patients homogeneously treated with the AIDA schedule were included in the study and prognostic correlation with respect to CD34 expression, both when expressed in association with CD2 and as isolated expression (cutoff ≥2 to <10 % or ≥10 %), were investigated. CD34 was associated to CD2 in 30 patients and was isolated in 19 patients. When compared to the CD34-negative population, CD34/CD2 expression identified a subgroup with characteristic features: M3 variant subtype (26 vs 7 % in the negative group, p = 0.02), bcr3 transcript subtype (73 vs 32 %, p = 0.001), high risk according to the risk of relapse (66 vs 17 %, p = 0.002), high incidence of differentiation syndrome (26 vs 12 %, p = 0.01), lower overall survival (88 vs 95 %), and a significantly higher rate of relapse (22 vs 13.8 %, p = 0.05). We then evaluated the prognostic value of isolated CD34 expression: it was detected in nine patients with a cutoff of expression ≥10 % and in 10 patients with a cutoff ≥2 but <10 %. Isolated CD34 positivity identified a subgroup with a classic morphology (79 %), bcr1 prevalence (53 %), higher rate of relapse (37 vs 13.8 % in the negative group, p = 0.002), higher incidence of differentiation syndrome (55 vs 12 %, p = 0.03), and lower overall survival (60 vs 95 %, p = 0.001). The results of our study confirm that CD34/CD2 expression characterizes a subset of APL with a high WBC count and a variant morphological subtype, associated with an unfavorable clinical course. We also show that the isolated expression of CD34, even at a low cutoff, identifies a group of classic APL with a negative prognosis. Further studies aimed at identifying other molecular signatures in CD34-positive patients are needed in order to optimize the therapeutic strategy for this subset of patients.

Tanaka S, Aida K, Nishida Y, Kobayashi T
Pathophysiological mechanisms involving aggressive islet cell destruction in fulminant type 1 diabetes.
Endocr J. 2013; 60(7):837-45 [PubMed] Related Publications
Fulminant type 1 diabetes is characterized by a rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetic complications. This review summarizes new findings related to the pathophysiology of accelerated β-cell failure in fulminant type 1 diabetes. Immunohistological examination revealed the presence of enterovirus in pancreatic islet cells and exocrine tissues and hyperexpression of pattern recognition receptors (PRRs) including melanoma differentiation-associated antigen 5 (MDA5), retinoic acid-inducible gene-I (RIG-I), Toll-like receptor (TLR)3 and TLR4, essential sensors of innate immunity, in islet cells and mononuclear cells (MNCs) infiltrating islets. Interferon (IFN)-α and IFN-β, products of PRR cascades, were expressed in both islet cells and infiltrating MNCs. Phenotypes of infiltrating cells around and/or into islets were mainly dendritic cells, macrophages and CD8+ T cells. Islet β-cells simultaneously expressed CXC chemokine ligand 10 (CXCL10), IFN-γ and interleukin-18, indicating that these chemokines/ cytotoxic cytokines mutually amplify their cytoplasmic expression in the islet cells. These positive feedback systems might enhance adaptive immunity, leading to rapid and complete loss of β-cells in fulminant type 1 diabetes. In innate and adaptive/autoimmune immune processes, the mechanisms behind bystander activation/killing might further amplify β-cell destruction. In addition to intrinsic pathway of cell apoptosis, the Fas and Fas ligand pathway are also involved as an extrinsic pathway of cell apoptosis. A high prevalence of anti-amylase autoantibodies was recognized in patients with fulminant type 1 diabetes, which suggests that Th2 T-cell reactive immunity against amylase might contribute to β-cell destruction in fulminant type 1 diabetes.

Arai T, Sakurai U, Sawabe M, et al.
Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach.
Gastric Cancer. 2013; 16(4):505-12 [PubMed] Related Publications
BACKGROUND: Microsatellite instability (MSI) has been observed in 8-39 % of sporadic gastric cancers. However, despite numerous reports indicating a significant relationship between intestinal-type histology and MSI, detailed correlation between histological subtypes and MSI remains obscure. The purpose of the present study is to clarify the relationship between histological subtype and microsatellite status in gastric carcinomas.
METHODS: Microsatellite status was examined for 464 consecutive gastric carcinomas from 420 patients as well as histological subtypes and other clinicopathological findings.
RESULTS: MSI was observed in 82 carcinomas (17.7 %), and the greatest proportions were observed in solid-type, poorly differentiated adenocarcinoma (43.0 %) and papillary adenocarcinoma (32.5 %), both being significantly higher than those of other subtypes. The proportion increased with advancing age (0 % at 51-64 years, 8.5 % at 65-74 years, 18.4 % at 75-84 years, 35.3 % at 85-96 years). Compared with microsatellite-stable carcinomas, microsatellite-unstable carcinomas were significantly related with older age, female gender, antral location, and predominant papillary adenocarcinoma and solid-type, poorly differentiated adenocarcinoma. Poorly differentiated type carcinoma was significantly less frequent than differentiated type in microsatellite-unstable cancer at the early stage, whereas no significant difference existed at the advanced stage.
CONCLUSIONS: These results suggest that there are specific histological subtypes with highly frequent MSI and that gastric carcinoma with MSI originates from differentiated-type carcinomas, indicating histological diversity during tumor growth.

Miyasaka T, Takeshima SN, Jimba M, et al.
Identification of bovine leukocyte antigen class II haplotypes associated with variations in bovine leukemia virus proviral load in Japanese Black cattle.
Tissue Antigens. 2013; 81(2):72-82 [PubMed] Related Publications
Bovine leukemia virus (BLV) is the etiological agent of enzootic bovine leukosis, which is the most common neoplastic disease of cattle. Bovine leukocyte antigen (BoLA) is strongly involved in the subclinical progression of BLV infections. Recent studies show that the BoLA-DRB3 gene might play a direct role in controlling the number of BLV-infected peripheral B lymphocytes in vivo in Holstein cattle. However, the specific BoLA class II allele and DRB3-DQA1 haplotypes determining the BLV proviral load in Japanese Black cattle are yet to be identified. In this study, we focused on the association of BLV proviral load and polymorphism of BoLA class II in Japanese Black cattle. We genotyped 186 BLV-infected, clinically normal cattle for BoLA-DRB3 and BoLA-DQA1 using a polymerase chain reaction-sequence-based typing method. BoLA-DRB3*0902 and BoLA-DRB3*1101 were associated with a low proviral load (LPVL), and BoLA-DRB3*1601 was associated with a high proviral load (HPVL). Furthermore, BoLA-DQA1*0204 and BoLA-DQA1*10012 were related to LPVL and HPVL, respectively. Furthermore, we confirmed the correlation between the DRB3-DQA1 haplotype and BLV proviral load. Two haplotypes, namely 0902B or C (DRB3*0902-DQA1*0204) and 1101A (DRB3*1101-DQA1*10011), were associated with a low BLV proviral load, whereas one haplotype 1601B (DRB3*1601-DQA1*10012) was associated with a high BLV proviral load. We conclude that resistance is a dominant trait and susceptibility is a recessive trait. Additionally, resistant alleles were common between Japanese Black and Holstein cattle, and susceptible alleles differed. This is the first report to identify an association between the DRB3-DQA1 haplotype and variations in BLV proviral load.

Tanaka M, Kato K, Gomi K, et al.
NUT midline carcinoma: report of 2 cases suggestive of pulmonary origin.
Am J Surg Pathol. 2012; 36(3):381-8 [PubMed] Related Publications
In this study, we report 2 pediatric cases of nuclear protein of the testis (NUT) midline carcinoma (NMC) suggestive of pulmonary origin: case 1 was a 14-year-old Japanese boy and case 2 was a 7-year-old Japanese girl. Initial symptoms of both cases were prolonged cough and chest pain, and the case 2 patient also complained of lumbago and lumbar mass due to bone metastases. Imaging studies revealed that pulmonary tumors from both patients were located at the hilar region of the lower lobe. Biopsies of the tumors showed undifferentiated carcinoma in case 1 and combined undifferentiated and squamous cell carcinoma in case 2. Despite intensive treatment with chemotherapy and radiation, progression of neither tumor was controlled, and both patients died of the tumors at 1 year (case 1) and 4 months (case 2) after onset of disease. Both tumors were diffusely positive for p63 and NUT expression and were partially positive for various cytokeratins. Reverse transcription polymerase chain reaction analysis and subsequent direct sequencing revealed that the bromodomain-containing protein 4-NUT chimeric gene was present in tumor tissue of both patients, leading to a diagnosis of NMC. The tumor cells of case 1 were also positive for thyroid transcription factor-1 expression, but those of case 2 were negative. Histologic examination of the surgically removed lung tumor of case 1 indicated that the origin of the tumor was basal cells of the bronchiolar epithelia.

Kitada K, Aida S, Aikawa S
Coamplification of multiple regions of chromosome 2, including MYCN, in a single patchwork amplicon in cancer cell lines.
Cytogenet Genome Res. 2012; 136(1):30-7 [PubMed] Related Publications
Coamplification of multiple segments of chromosome 2, including an MYCN-bearing segment, was examined in 2 cancer cell lines, NCI-H69 (lung cancer) and IMR-32 (neuroblastoma). High-resolution array-CGH analysis revealed 13 and 6 highly amplified segments located at different sites in chromosome 2 in NCI-H69 and IMR-32, respectively. FISH analysis demonstrated that these segments were co-localized in double minutes in NCI-H69 and in homogeneously staining regions in IMR-32. Connectivity of the segments was determined by a PCR assay using designed primer sets. It was found that all the segments were connected to each other irrespective of their order and orientation against the genome sequence, and a single chain-like cluster was configured in both cell lines. Such patchwork structures of the amplicons suggest the possibility that massive genomic rearrangements, explained by the single catastrophic event model, are involved in the formation of the amplicons, enabling the coamplification of different chromosomal regions including the MYCN locus. The model comprises massive fragmentation of chromosomes and random rejoining of the fragments.

Udagawa T, Narumi K, Goto N, et al.
Syngeneic hematopoietic stem cell transplantation enhances the antitumor immunity of intratumoral type I interferon gene transfer for sarcoma.
Hum Gene Ther. 2012; 23(2):173-86 [PubMed] Related Publications
Sarcoma at advanced stages remains a clinically challenging disease. Interferons (IFNs) can target cancer cells by multiple antitumor activities, including the induction of cancer cell death and enhancement of immune response. However, the development of an effective cancer immunotherapy is often difficult, because cancer generates an immunotolerant microenvironment against the host immune system. An autologous hematopoietic stem cell transplantation (HSCT) is expected to reconstitute a fresh immune system, and expand tumor-specific T cells through the process of homeostatic proliferation. Here we examined whether a combination of autologous HSCT and IFNs could induce an effective tumor-specific immune response against sarcoma. First, we found that a type I IFN gene transfer significantly suppressed the cell growth of various sarcoma cell lines, and that IFN-β gene transfer was more effective in inducing cell death than was IFN-α in sarcoma cells. Then, to examine the antitumor effect in vivo, human sarcoma cells were inoculated in immune-deficient mice, and a lipofection of an IFN-β-expressing plasmid was found to suppress the growth of subcutaneous tumors significantly. Finally, the IFN gene transfer was combined with syngeneic HSCT in murine osteosarcoma models. Intratumoral IFN-β gene transfer markedly suppressed the growth of vector-injected tumors and inhibited formation of spontaneous lung and liver metastases in syngeneic HSCT mice, and an infiltration of many immune cells was recognized in metastatic tumors of the treated mice. The treated mice showed no significant adverse events. A combination of intratumoral IFN gene transfer with autologous HSCT could be a promising therapeutic strategy for patients with sarcoma.

Avvisati G, Lo-Coco F, Paoloni FP, et al.
AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance.
Blood. 2011; 117(18):4716-25 [PubMed] Related Publications
All-trans-retinoic acid (ATRA) has greatly modified the prognosis of acute promyelocytic leukemia; however, the role of maintenance in patients in molecular complete remission after consolidation treatment is still debated. From July 1993 to May 2000, 807 genetically proven newly diagnosed acute promyelocytic leukemia patients received ATRA plus idarubicin as induction, followed by 3 intensive consolidation courses. Thereafter, patients reverse-transcribed polymerase chain reaction-negative for the PML-RARA fusion gene were randomized into 4 arms: oral 6-mercaptopurine and intramuscular methotrexate (arm 1); ATRA alone (arm 2); 3 months of arm1 alternating to 15 days of arm 2 (arm 3); and no further therapy (arm 4). Starting from February 1997, randomization was limited to ATRA-containing arms only (arms 2 and 3). Complete remission was achieved in 761 of 807 (94.3%) patients, and 681 completed the consolidation program. Of these, 664 (97.5%) were evaluated for the PML-RARA fusion gene, and 586 of 646 (90.7%) who tested reverse-transcribed polymerase chain reaction-negative were randomized to maintenance. The event-free survival estimate at 12 years was 68.9% (95% confidence interval, 66.4%-71.4%), and no differences in disease-free survival at 12 years were observed among the maintenance arms.

Ferrara F, Finizio O, Izzo T, et al.
Autologous stem cell transplantation for patients with acute promyelocytic leukemia in second molecular remission.
Anticancer Res. 2010; 30(9):3845-9 [PubMed] Related Publications
Relapse still occurs in approximately 20-30% of patients with acute promyelocytic leukemia (APL) and, after achievement of second complete remission (CR), the optimal strategy is still controversial. We describe therapeutic results from a series of 13 patients autografted in second molecular remission (MR) by a molecular negative apheresis product. In all patients, the disease was confirmed at the molecular level and all had received the GIMEMA/AIDA protocol, achieving molecular remission at the end of consolidation. Relapse was hematological in 12 cases and molecular in one. After consolidation with chemotherapy, all patients achieved MR and received a further course plus granulocyte-colony stimulating factor as mobilizing therapy. A median of 7.6×10(6) (range 2.7-10) CD34-positive cells/kg were collected. In all cases, molecular evaluation of the apheresis product was negative for the promyelocytic leukemia/retinoic acid receptor alpha gene. No case of transplant-related mortality was recorded. No maintenance or consolidation therapy after autologous stem cell transplantation (ASCT) was given to any patient. After a median follow-up of 25 months from ASCT, 10 patients are alive in sustained MR, while two relapsed after ASCT and died in the setting of refractory disease; one patient achieved a third CR and is waiting for allogeneic SCT. These results suggest that ASCT performed with a molecularly negative graft in APL patients in second MR offers a valid chance for achieving a cure. Such an approach should also be considered in relapsed patients with an HLA-compatible donor, namely in those with a first CR lasting more than one year or in unfit or elderly individuals.

Arai T, Kasahara I, Sawabe M, et al.
Role of methylation of the hMLH1 gene promoter in the development of gastric and colorectal carcinoma in the elderly.
Geriatr Gerontol Int. 2010; 10 Suppl 1:S207-12 [PubMed] Related Publications
The occurrence of malignant neoplasms increases with advancing age. Although aging and carcinogenesis are basically different processes, they share phenomena such as the accumulation of DNA damage and abnormal proteins. Recent advances in molecular biology have shown an accumulation of genetic and epigenetic changes in both aging and carcinogenesis, as well as the alteration of metabolism, immunosenescence and shortened telomeres. DNA methylation is a representative epigenetic phenomenon and is frequently involved in controlling gene functions during development and tumorigenesis. We herein focused on methylation of genes in the development of gastrointestinal carcinomas in the elderly. The proportion of gastric and colorectal carcinomas with hypermethylation of the hMLH1 promoter increases with age, reaching 25-30% of all carcinomas of the stomach and large intestine in elderly patients. These tumors have clinicopathological and molecular characteristics such as loss of hMLH1 expression, microsatellite instability, poorly differentiated histology, peritumoral inflammatory cell infiltration, low incidence of lymph node metastasis and favorable prognosis. However, methylation-related carcinogenesis accounts for up to approximately one-third of tumors, and other mechanisms; for example chromosomal instability as a result of telomere dysfunction, are responsible for the development of most carcinomas in the elderly.

Miyai K, Yamamoto S, Aida S, et al.
Massive intra-abdominal undifferentiated carcinoma derived from an endometrioid adenocarcinoma in a "normal-sized" ovary.
Int J Gynecol Pathol. 2010; 29(4):321-7 [PubMed] Related Publications
We report a case of massive intra-abdominal undifferentiated carcinoma derived from a tiny well-differentiated endometrioid adenocarcinoma of the ovary. The patient, a 56-year-old woman, who presented with a large intra-abdominal mass, underwent cytoreductive surgery with hysterectomy and bilateral salpingo-oophorectomy. Macroscopically, the intra-abdominal mass was composed of fragile and solid tumor components with extensive necro-hemorrhagic areas, mimicking a primary peritoneal tumor. Both ovaries were apparently normal in size, but a cut section of the right ovary revealed a 2-cm solid and cystic tumor showing focal rupture to the peritoneal surface. The intra-abdominal tumor consisted of pleomorphic cells without specific differentiation, showing diffuse sheet-like proliferation. The right ovarian tumor was a histologically well-differentiated endometrioid adenocarcinoma. Both the intra-abdominal undifferentiated tumor and the ovarian adenocarcinoma cells were immunohistochemically positive for keratin AE1/3, Ber-EP4, and CD10. Epithelial membrane antigen was positive only in the ovarian adenocarcinoma component, and vimentin was diffusely positive only in the intra-abdominal undifferentiated tumor component. Calretinin was negative in both tumor components. Allelotype analysis using 24 polymorphic markers located on 12 chromosomal arms showed that the intra-abdominal undifferentiated carcinoma and ovarian adenocarcinoma components had a high concordance rate (88%) of allelic patterns including identical allelic loss patterns at 7 chromosomal loci, suggesting a common genetic lineage. These data suggest that ovarian endometrioid adenocarcinoma, even when small in size, can give rise to a massive undifferentiated carcinoma filling the peritoneal cavity.

Ogata S, Ozeki Y, Nakanishi K, et al.
A pilot study of mRNA expressions of 5-fluorouracil pathway genes in peripheral blood mononuclear cells and tumor tissues in patients with lung adenocarcinoma.
Lung Cancer. 2011; 71(2):199-204 [PubMed] Related Publications
To assess whether early lung cancer prediction might be informed by an mRNA assay for 5-fluorouracil pathway genes in peripheral blood mononuclear cells (PBMNCs), we examined specimens taken from 51 adenocarcinoma patients and 38 controls (including six patients with benign tumors). PBMNCs and tumor-tissue specimens were taken for measurement of the mRNAs of various 5-fluorouracil pathway genes [thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and orotate phosphoribosyl transferase (OPRT)]. By quantitative RT-PCR, all four mRNAs were detected in both PBMNCs and tumor tissues. In PBMNCs, TS mRNA/GAPDH mRNA levels were significantly higher in adenocarcinoma patients than in the controls, and significantly higher for pathological stages 2-4 and lymph-node involvement pN1-pN3 than for pathological stage 1 and pN0, respectively. No correlation between PBMNCs and tumor-tissue specimens was found for the level of any mRNA. Thus, the measurement of TS mRNA in PBMNCs might aid the diagnosis of lung adenocarcinoma.

Kawasaki T, Yokoi S, Tsuda H, et al.
BCL2L2 is a probable target for novel 14q11.2 amplification detected in a non-small cell lung cancer cell line.
Cancer Sci. 2007; 98(7):1070-7 [PubMed] Related Publications
Amplification of chromosomal DNA is thought to be one of the mechanisms that activates cancer-related genes in tumors. In a previous genome-wide screening of DNA copy number aberrations in a panel of non-small cell lung cancer (NSCLC) cell lines using an in-house bacterial artificial chromosome-based array, we identified a novel amplification at 14q11.2 in HUT29 cells derived from human lung adenocarcinoma. To identify the most likely target for the 14q11.2 amplification, we determined the extent of the amplicon by fluorescence in situ hybridization and then analyzed NSCLC cell lines for the expression levels of 28 genes present within the 1-Mb amplified region. Significant overexpression in the HUT29 cell line with amplification, relatively frequent overexpression in additional NSCLC cell lines compared with an immortalized normal lung epithelial cell line, and reported information about the function of each candidate gene prompted us to characterize the BCL2-like2 (BCL2L2) gene, a prosurvival member of the BCL2 family, as the most likely target for the 14q11.2 amplicon. Immunohistochemical analysis of 61 primary cases of lung adenocarcinoma demonstrated that BCL2L2 overexpression was significantly associated with tumor stage and differentiation status, and tended to be associated with a poorer prognosis. Downregulation of BCL2L2 expression using small interfering RNA dramatically inhibited the growth of HUT29 cells, but showed no effect on anticancer reagent-induced cell death of the same cell line. These findings demonstrate that overexpressed BCL2L2, through amplification or other mechanisms, promotes the growth of NSCLC, especially the adenocarcinoma subtype, and might be a therapeutic target.

Santamaría C, Chillón MC, Fernández C, et al.
Using quantification of the PML-RARalpha transcript to stratify the risk of relapse in patients with acute promyelocytic leukemia.
Haematologica. 2007; 92(3):315-22 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: The detection of PML-RARalpha by real-time polymerase chain reaction (RQ-PCR) is becoming an important tool for monitoring minimal residual disease (MRD) in patients with acute promyelocytic leukemia (APL). However, its clinical value remains to be determined. Our aim was to analyze any associations between the risk of relapse and RQ-PCR results in different phases of treatment, comparing these data with those yielded by conventional qualitative reverse transcriptase-PCR.
DESIGN AND METHODS: Follow-up samples from 145 APL patients treated with the PETHEMA protocols were evaluated by the RQ-PCR protocol (Europe Against Cancer program) and by the RT-PCR method (BIOMED-1 Concerted Action). Hematologic and molecular relapses and relapse-free survival were recorded. We then looked for associations between relapse risk and RQ-PCR results.
RESULTS: After induction therapy, no association was found between positive RQ-PCR results and relapse. The PCR result here did not imply any change in the scheduled therapy. After the third consolidation course, two out of three cases with positive RQ-PCR relapsed in contrast to 16 out of 119 (13%) patients with negative RQ-PCR. During maintenance therapy and out-of treatment, all patients with >10 PML-RARalpha normalized copy number (NCN) (n=19) relapsed while all patients with <1 NCN at the end of the study remained in hematologic remission (p<0.0001). In the intermediate group (NCN 1-10) (n=18), the relapse-free survival at 5 years was 60%. Hematologic relapses were predicted if a positive RQ-PCR result had been obtained in a follow-up sample within the previous 4 months.
INTERPRETATION AND CONCLUSIONS: Based on the information provided by RQ-PCR in samples obtained after the end of consolidation and subsequently, a relapse risk stratification could be established for APL patients. This stratification divides patients into three groups: those at high risk of relapse, those with an intermediate risk and those with a low risk of relapse.

Arai T, Kasahara I, Sawabe M, et al.
Microsatellite-unstable mucinous colorectal carcinoma occurring in the elderly: comparison with medullary type poorly differentiated adenocarcinoma.
Pathol Int. 2007; 57(4):205-12 [PubMed] Related Publications
Mucinous carcinoma and poorly differentiated adenocarcinoma of the large intestine have a high frequency of microsatellite instability, and their occurrence increases gradually with age. To elucidate the clinicopathological and immunohistochemical features of microsatellite-unstable mucinous carcinoma and compare the tumor with medullary type poorly differentiated adenocarcinoma, the clinicopathological status and expression of mucin core and hMLH1 proteins were studied in 15 microsatellite-unstable and 20 microsatellite-stable mucinous colorectal carcinomas occurring in elderly patients, and compared with 23 cases of medullary type poorly differentiated adenocarcinoma in which 21 cases were microsatellite-unstable. Thirteen (87%) of 15 microsatellite-unstable carcinomas exhibited absent hMLH1 expression compared with three (15%) of 20 microsatellite-stable carcinomas (P < 0.01). The proportion (87%) of positive MUC5AC expression in microsatellite-unstable mucinous carcinoma was significantly higher than that (45%) in microsatellite-stable mucinous carcinoma (P = 0.01). Compared with microsatellite-stable mucinous carcinoma, microsatellite-unstable mucinous carcinomas were significantly associated with a proximal location, intra- and peritumoral inflammatory cell infiltration, frequent MUC5AC expression, a low incidence of lymph node metastasis and absent hMLH1 protein expression, which is not different to medullary type poorly differentiated adenocarcinoma except for MUC2 expression and age-related occurrence. These results suggest that microsatellite-unstable mucinous carcinoma occurring in the elderly shares clinicopathological and molecular features with medullary type poorly differentiated adenocarcinoma and that microsatellite instability with absent hMLH1 expression plays an important role in the development of these two carcinomas.

Arai T, Sugai T, Kasahara I, et al.
Age-related alteration in the association of microsatellite instability with absent hMLH1 expression and histological types of colorectal carcinoma.
Pathol Int. 2006; 56(10):597-603 [PubMed] Related Publications
Microsatellite instability (MSI) is present in approximately 15-20% of sporadic colorectal cancers. However, despite the increased prevalence of absent hMLH1 expression and MSI in colorectal cancer in the elderly, few attempts have been made to define it in detail. The aim of the present paper was to correlate age-related alterations in absent hMLH1 expression and MSI with various histological types of colorectal carcinoma. hMLH1 expression and microsatellite status were studied in 184 colorectal carcinomas (49 well-differentiated, 49 moderately differentiated, 49 poorly differentiated adenocarcinomas, and 37 mucinous carcinomas). The prevalence of absent hMLH1 expression was higher in poorly differentiated adenocarcinoma (63%) and mucinous carcinoma (43%) than in well- (8%) and moderately (12%) differentiated adenocarcinomas. MSI was found more frequently in poorly differentiated adenocarcinoma (69%) and mucinous carcinoma (41%) than in well- and moderately differentiated adenocarcinomas (8% and 6%, respectively). Age-related differences in absent hMLH1 expression and MSI were found only in poorly differentiated adenocarcinoma, in which the prevalence of medullary-type carcinoma increased with advancing age. These results indicate that an age-related increase of medullary-type tumors in poorly differentiated adenocarcinoma may play an important role in the increase of absent hMLH1 expression and MSI in colorectal carcinoma.

Dowa Y, Yamamoto T, Abe Y, et al.
Congenital neuroblastoma in a patient with partial trisomy of 2p.
J Pediatr Hematol Oncol. 2006; 28(6):379-82 [PubMed] Related Publications
We report the fourth example of a patient with germline partial trisomy of 2p21-pter and congenital neuroblastoma. The male infant had a dysmorphic facial expression and presented with congenital heart disease, supernumerary nipples, hypospadias, shawl scrotum, hemilateral persistent hyperplastic primary vitreous, and neuroblastoma. His germline karyotype of 46,XY,der(8)t(2;8)(p21;p23.2) was inherited from a maternal-balanced translocation, which indicates that the proto-oncogene MYCN region of 2p24.3 is tripicated in germline cells. A cytogenetic study of the biopsied tumor cells did not show MYCN amplification, but the DNA index was 2.4 and histologic fluorescent in situ hybridization analysis indicated somatic mutation with near-pentaploidy of the tumor cells. This could be an alternative mechanism of MYCN activation in the process of the tumorigenesis of neuroblastoma.

Yamamoto G, Irie T, Aida T, et al.
Correlation of invasion and metastasis of cancer cells, and expression of the RAD21 gene in oral squamous cell carcinoma.
Virchows Arch. 2006; 448(4):435-41 [PubMed] Related Publications
Although RAD21 is involved in the repair of double-strand breaks in DNA and is essential for mitotic growth, its role in cancer has been unclear. In this study, the relevance of RAD21 gene expression to the invasion and metastasis of oral squamous cell carcinoma was clarified using laser microdissection and real-time polymerase chain reaction (PCR). Using two different metastatic potential oral squamous cells [high-metastatic-potential squamous cell carcinoma cells (SAS-Ly) and low-metastatic-potential squamous cell carcinoma cells (SAS)], the relation of RAD21 gene expression to apoptosis, invasion, and metastasis was examined. The results showed that RAD21 gene expression was significantly decreased in oral squamous cell carcinoma when it expressed the INFbeta and INFgamma invasion patterns in comparison with the INFalpha invasion pattern (p<0.01). In addition, in comparison with SAS cells, SAS-Ly cells indicated tolerance to cell death induced by an apoptosis induction reagent, while the expression level of the RAD21 gene in SAS cells was increased by the apoptosis induction reagent. However, in SAS-Ly cells, the reagent induced no significant difference. Our findings indicate that the RAD21 gene was closely related to the invasion and metastasis of cancer cells.

Salameh A, Dhein S
Pharmacology of gap junctions. New pharmacological targets for treatment of arrhythmia, seizure and cancer?
Biochim Biophys Acta. 2005; 1719(1-2):36-58 [PubMed] Related Publications
Intercellular communication in many organs is maintained via intercellular gap junction channels composed of connexins, a large protein family with a number of isoforms. This gap junction intercellular communication (GJIC) allows the propagation of action potentials (e.g., in brain, heart), and the transfer of small molecules which may regulate cell growth, differentiation and function. The latter has been shown to be involved in cancer growth: reduced GJIC often is associated with increased tumor growth or with de-differentiation processes. Disturbances of GJIC in the heart can cause arrhythmia, while in brain electrical activity during seizures seems to be propagated via gap junction channels. Many diseases or pathophysiological conditions seem to be associated with alterations of gap junction protein expression. Thus, depending on the target disease opening or closure of gap junctions may be of interest, or alteration of connexin expression. GJIC can be affected acutely by changing gap junction conductance or--more chronic--by altering connexin expression and membrane localisation. This review gives an overview on drugs affecting GJIC.

Kaul SC, Aida S, Yaguchi T, et al.
Activation of wild type p53 function by its mortalin-binding, cytoplasmically localizing carboxyl terminus peptides.
J Biol Chem. 2005; 280(47):39373-9 [PubMed] Related Publications
The Hsp70 family member mortalin (mot-2/mthsp70/GRP75) binds to a carboxyl terminus region of the tumor suppressor protein p53. By in vivo co-immunoprecipitation of mot-2 with p53 and its deletion mutants, we earlier mapped the mot-2-binding site of p53 to its carboxyl terminus 312-352 amino acid residues. In the present study we attempted to disrupt mot-2-p53 interactions by overexpression of short p53 carboxyl-terminal peptides. We report that p53 carboxyl-terminal peptides (amino acid residues 312-390, 312-352, 323-390, and 323-352) localize in the cytoplasm, whereas 312-322, 337-390, 337-352, and 352-390 locate mostly in the nucleus. Most interestingly, the cytoplasmically localizing p53 peptides harboring the residues 323-337 activated the endogenous p53 function by displacing it from p53-mortalin complexes and relocating it to the nucleus. Such activation of p53 function was sufficient to cause growth arrest of human osteosarcoma and breast carcinoma cells.

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