HSPA8

Gene Summary

Gene:HSPA8; heat shock 70kDa protein 8
Aliases: LAP1, HSC54, HSC70, HSC71, HSP71, HSP73, LAP-1, NIP71, HEL-33, HSPA10, HEL-S-72p
Location:11q24.1
Summary:This gene encodes a member of the heat shock protein 70 family, which contains both heat-inducible and constitutively expressed members. This protein belongs to the latter group, which are also referred to as heat-shock cognate proteins. It functions as a chaperone, and binds to nascent polypeptides to facilitate correct folding. It also functions as an ATPase in the disassembly of clathrin-coated vesicles during transport of membrane components through the cell. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:heat shock cognate 71 kDa protein
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
Show (38)
Pathways:What pathways are this gene/protein implicaed in?
Show (2)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 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.

  • Gene Expression Profiling
  • Transduction
  • Proteomics
  • Skin Cancer
  • Squamous Cell Carcinoma
  • RT-PCR
  • HSC70 Heat-Shock Proteins
  • Molecular Sequence Data
  • Heat-Shock Proteins
  • alpha Karyopherins
  • Neoplasm Proteins
  • Microarray Analysis
  • Chromosome 11
  • Cell Line
  • Tumor Markers
  • Carrier Proteins
  • Messenger RNA
  • Electrophoresis, Gel, Two-Dimensional
  • HSPA8
  • Benzoquinones
  • Cancer Gene Expression Regulation
  • U937 Cells
  • HSP70 Heat-Shock Proteins
  • Breast Cancer
  • Down-Regulation
  • Genetic Markers
  • Cell Cycle
  • Up-Regulation
  • Cell Survival
  • Melanoma
  • Oligonucleotide Array Sequence Analysis
  • RTPCR
  • HSP90 Heat-Shock Proteins
  • Base Sequence
  • Gene Expression
  • siRNA
  • Cervical Cancer
  • Vitamin D3 24-Hydroxylase
  • p53 Protein
  • Transfection
  • Cancer RNA
Tag cloud generated 27 February, 2015 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: HSPA8 (cancer-related)

Liu Q, Boudot A, Ni J, et al.
Cyclin D1 and C/EBPβ LAP1 operate in a common pathway to promote mammary epithelial cell differentiation.
Mol Cell Biol. 2014; 34(16):3168-79 [PubMed] Free Access to Full Article Related Publications
Both cyclin D1 and the transcription factor C/EBPβ are required for mammary epithelial cell differentiation; however, the pathway in which they operate is uncertain. Previous analyses of the patterns of gene expression in human tumors suggested a connection between cyclin D1 overexpression and C/EBPβ, but whether this represents a cancer-specific gain of function for cyclin D1 is unknown. C/EBPβ is an intronless gene encoding three protein isoforms--LAP1, LAP2, and LIP. Here, we provide evidence that cyclin D1 engages C/EBPβ in an isoform-specific manner. Cyclin D1 binds to LAP1, an event that activates the transcriptional function of LAP1 by relieving its autoinhibited state effected by intramolecular interactions. Reexpression of LAP1 but not LAP2 or LIP restores the ability of C/EBPβ-deficient mammary epithelial cells to differentiate and does so in a manner dependent on cyclin D1. And cyclin D1-mediated activation of LAP1 participates in mammary epithelial cell differentiation. Our findings indicate that cyclin D1 and C/EBPβ LAP1 operate in a common pathway to promote mammary epithelial cell differentiation.

Wang H, Song Y, Hao D, et al.
Ultrasound-targeted microbubble destruction combined with dual targeting of HSP72 and HSC70 inhibits HSP90 function and induces extensive tumor-specific apoptosis.
Int J Oncol. 2014; 45(1):157-64 [PubMed] Related Publications
The specific and efficient delivery of small interfering RNA (siRNA) into cancer cells in vivo remains a major obstacle. In this study, we investigated whether ultrasound-targeted microbubble destruction (UTMD) combined with dual targeting of HSP72 and HSC70 in prostate cancer cell lines improve the specific and efficient cell uptake of siRNA, inhibit HSP90 function and induce extensive tumor-specific apoptosis. VCaP cells were transfected with siRNA oligonucleotides. Cell viability assays were used to evaluate the safety of UTMD. The expression of HSP70, HSP90, caspase-8, caspase-3, PARP-1 and cleaved caspase-3 were determined by quantitative PCR and western blotting. Apoptosis and transfection efficiency were detected by flow cytometry. We found that HSP72, HSC70 and HSP90 expression was absent or weak in normal prostate epithelial cells (RWPE-1), and became uniformly and strongly expressed in prostate cancer cells (VCaP). VCaP and RWPE-1 cells expressed very low levels of caspase-8, caspase-3, PARP-1 and cleaved caspase-3. UTMD combined with dual targeting of HSP72 and HSC70 siRNA impoved the efficiency of transfection, cell uptake of siRNA, downregulated HSP70 and HSP90 expression in VCaP cells on the mRNA and protein levels, and upregulated major apoptotic markers (PARP-1, caspase-8, caspase-3 and cleaved caspase-3), thus, inducing extensive tumor-specific apoptosis. The Cell Counting Kit-8 assay showed decreased cellular viability in the HSP72/HSC70-siRNA silenced group. These results suggest that the combination of UTMD with dual targeting of HSP72 and HSC70 may improve the specific and efficient cell uptake of siRNA, inhibit HSP90 function and induce extensive tumor-specific apoptosis, indicating a novel, potential means for targeting therapeutic strategy to prostate cancer cells.

Tan S, Ding K, Li R, et al.
Identification of miR-26 as a key mediator of estrogen stimulated cell proliferation by targeting CHD1, GREB1 and KPNA2.
Breast Cancer Res. 2014; 16(2):R40 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Estrogen signaling is pivotal in the progression of estrogen receptor positive breast cancer primarily by the regulation of cell survival and proliferation. Micro (mi)RNAs have been demonstrated to be regulated by estrogen to mediate estrogenic effects. Herein, we determined the role of estrogen regulated miR-26 and its underlying molecular mechanisms associated with estrogen receptor (ER)+ breast cancer proliferation.
METHODS: The expression of miR-26a and miR-26b was evaluated by real-time quantitative (RT)-PCR. The expression of miR-26a or miR-26b was modulated in ER+ breast cancer cells (MCF-7 and T47D) and tumor cell growth in vitro and an in vivo xenograft model was determined. Bioinformatics analyses were utilized to screen for estrogen responsive genes, which were also predicted to be targeted by miR-26. Luciferase reporter assays were performed to confirm miR-26 regulation of the 3' UTR of target genes. The levels of miR-26 target genes (CHD1, GREB1 and KPNA2) were evaluated by western blotting and immunohistochemistry.
RESULTS: Estrogen reduced the expression of miR-26a and miR-26b in ER+ breast cancer cells. Forced expression of miR-26a or miR-26b significantly inhibited the estrogen stimulated growth of ER+ breast cancer cells and tumor growth in xenograft models, whereas miR-26a/b depletion increased the growth of ER+ breast cancer cells in the absence of estrogen treatment. Screening of estrogen responsive genes, which were also predicted to be targeted by miR-26, identified GREB1 and nine other genes (AGPAT5, AMMECR1, CHD1, ERLIN1, HSPA8, KPNA2, MREG, NARG1, and PLOD2). Further verification has identified nine genes (AGPAT5, CHD1, ERLIN1, GREB1, HSPA8, KPNA2, MREG, NARG1 and PLOD2) which were directly targeted by miR-26 via their 3' UTR. Functional screening suggested only three estrogen regulated miR-26 target genes (CHD1, GREB1 and KPNA2) were involved in the regulation of estrogen promoted cell proliferation. Depletion of either CHD1, GREB1 or KPNA2 significantly abrogated the enhanced growth of ER+ breast cancer cells due to miR-26 depletion. We further demonstrated that estrogen stimulated c-MYC expression was both sufficient and necessary for the diminished expression of miR-26a and miR-26b.
CONCLUSIONS: We have identified a novel estrogen/MYC/miR-26 axis that mediates estrogen stimulated cell growth via CHD1, GREB1 and KPNA2.

Adam C, Baeurle A, Brodsky JL, et al.
The HSP70 modulator MAL3-101 inhibits Merkel cell carcinoma.
PLoS One. 2014; 9(4):e92041 [PubMed] Free Access to Full Article Related Publications
Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited in vivo antitumor activity in an MCC xenograft model suggesting that this substance or related compounds are potential therapeutics for the treatment of MCC in the future.

Karantanos T, Tanimoto R, Edamura K, et al.
Systemic GLIPR1-ΔTM protein as a novel therapeutic approach for prostate cancer.
Int J Cancer. 2014; 134(8):2003-13 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
GLIPR1 is a p53 target gene known to be downregulated in prostate cancer, and increased endogenous GLIPR1 expression has been associated with increased production of reactive oxygen species, increased apoptosis, decreased c-Myc protein levels and increased cell cycle arrest. Recently, we found that upregulation of GLIPR1 in prostate cancer cells increases mitotic catastrophe through interaction with heat shock cognate protein 70 (Hsc70) and downregulation of Aurora kinase A and TPX2. In this study, we evaluated the mechanisms of recombinant GLIPR1 protein (glioma pathogenesis-related protein 1-transmembrane domain deleted [GLIPR1-ΔTM]) uptake by prostate cancer cells and the efficacy of systemic GLIPR1-ΔTM administration in a prostate cancer xenograft mouse model. GLIPR1-ΔTM was selectively internalized by prostate cancer cells, leading to increased apoptosis through reactive oxygen species production and to decreased c-Myc protein levels. Interestingly, GLIPR1-ΔTM was internalized through clathrin-mediated endocytosis in association with Hsc70. Systemic administration of GLIPR1-ΔTM significantly inhibited VCaP xenograft growth. GLIPR1-ΔTM showed no evidence of toxicity following elimination from mouse models 8 hr after injection. Our results demonstrate that GLIPR1-ΔTM is selectively endocytosed by prostate cancer cells, leading to increased reactive oxygen species production and apoptosis, and that systemic GLIPR1-ΔTM significantly inhibits growth of VCaP xenografts without substantial toxicity.

Lv Y, Song S, Zhang K, et al.
CHIP regulates AKT/FoxO/Bim signaling in MCF7 and MCF10A cells.
PLoS One. 2013; 8(12):e83312 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
A number of studies have shown that apoptosis resistance can be observed in multiple human tumors; however the detailed mechanism remains unclear. In the present study, we demonstrated that the abnormal overexpression of the C terminus of Hsc70-interacting protein (CHIP) induced apoptosis resistance by regulating the AKT/FoxO/Bim signaling pathway in the breast cancer cell MCF7 and the human non-tumorigenic cell MCF10A. We found that CHIP overexpression in MCF7 and MCF10A cells activated AKT and inhibited the Forkhead box O (FoxO) transcription factors FoxO1, FoxO3, and FoxO4, thereby inhibiting transcription of the target genes bim and pten. Inhibition of PI3K by a chemical reagent revealed that these events may be critical for CHIP-induced apoptosis resistance. We also determined that inhibition of FoxO3 by CHIP led to the decrease in PTEN and further activated the AKT survival pathway. We corroborated our findings in breast cancer tissues. In general, the CHIP-modulated AKT/FoxO/Bim signaling pathway was shown to induce apoptosis resistance by decreasing the protein level of the tumor suppressor PTEN in both transcriptional and post-translational regulations.

Wang Y, Ren F, Wang Y, et al.
CHIP/Stub1 functions as a tumor suppressor and represses NF-κB-mediated signaling in colorectal cancer.
Carcinogenesis. 2014; 35(5):983-91 [PubMed] Related Publications
The carboxyl terminus of Hsc70-interacting protein (CHIP, also named Stub1), a U-box containing E3 ubiquitin ligase, is involved in degradation of certain oncogenic proteins. Recent studies indicated that CHIP suppresses tumor progression in human cancers by targeting Src-3, hypoxia inducible factor 1α, NF-κB, ErbB2 and c-Myc. Here, we report that CHIP was downregulated, predominantly, in the late stages of human colorectal cancer (CRC), and that the CHIP promoter was hypermethylated in CRC specimens. Overexpression of CHIP in HCT-116 cells resulted in impaired tumor growth in nude mice and decreased abilities of tumor cell migration and invasion. Conversely, depletion of CHIP in HCT-116 cells promoted tumor growth and increased tumor cell migration and invasion. CHIP was further found to negatively regulate NF-κB signaling in HCT-116 cells by promoting ubiquitination and degradation of p65, a subunit of the NF-κB complex. The suppressive effect of CHIP led to decreased expression of NF-κB-targeted oncogenes including Cyclin D1, c-Myc, MMP-2, VEGF and IL-8. We proposed that CHIP inhibits the malignancy of CRC cells, possibly through targeting NF-κB signaling. This study provides functional evidence for CHIP as a potential tumor suppressor in CRC, and CHIP expression may be a marker for stages of CRC.

Fang BA, Kovačević Ž, Park KC, et al.
Molecular functions of the iron-regulated metastasis suppressor, NDRG1, and its potential as a molecular target for cancer therapy.
Biochim Biophys Acta. 2014; 1845(1):1-19 [PubMed] Related Publications
N-myc down-regulated gene 1 (NDRG1) is a known metastasis suppressor in multiple cancers, being also involved in embryogenesis and development, cell growth and differentiation, lipid biosynthesis and myelination, stress responses and immunity. In addition to its primary role as a metastasis suppressor, NDRG1 can also influence other stages of carcinogenesis, namely angiogenesis and primary tumour growth. NDRG1 is regulated by multiple effectors in normal and neoplastic cells, including N-myc, histone acetylation, hypoxia, cellular iron levels and intracellular calcium. Further, studies have found that NDRG1 is up-regulated in neoplastic cells after treatment with novel iron chelators, which are a promising therapy for effective cancer management. Although the pathways by which NDRG1 exerts its functions in cancers have been documented, the relationship between the molecular structure of this protein and its functions remains unclear. In fact, recent studies suggest that, in certain cancers, NDRG1 is post-translationally modified, possibly by the activity of endogenous trypsins, leading to a subsequent alteration in its metastasis suppressor activity. This review describes the role of this important metastasis suppressor and discusses interesting unresolved issues regarding this protein.

Edwards SK, Moore CR, Liu Y, et al.
N-benzyladriamycin-14-valerate (AD 198) exhibits potent anti-tumor activity on TRAF3-deficient mouse B lymphoma and human multiple myeloma.
BMC Cancer. 2013; 13:481 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
BACKGROUND: TRAF3, a new tumor suppressor identified in human non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), induces PKCδ nuclear translocation in B cells. The present study aimed to evaluate the therapeutic potential of two PKCδ activators, N-Benzyladriamycin-14-valerate (AD 198) and ingenol-3-angelate (PEP005), on NHL and MM.
METHODS: In vitro anti-tumor activities of AD 198 and PEP005 were determined using TRAF3-/- mouse B lymphoma and human patient-derived MM cell lines as model systems. In vivo therapeutic effects of AD 198 were assessed using NOD SCID mice transplanted with TRAF3-/- mouse B lymphoma cells. Biochemical studies were performed to investigate signaling mechanisms induced by AD 198 or PEP005, including subcellular translocation of PKCδ.
RESULTS: We found that AD 198 exhibited potent in vitro and in vivo anti-tumor activity on TRAF3-/- tumor B cells, while PEP005 displayed contradictory anti- or pro-tumor activities on different cell lines. Detailed mechanistic investigation revealed that AD 198 did not affect PKCδ nuclear translocation, but strikingly suppressed c-Myc expression and inhibited the phosphorylation of ERK, p38 and JNK in TRAF3-/- tumor B cells. In contrast, PEP005 activated multiple signaling pathways in these cells, including PKCδ, PKCα, PKCε, NF-κB1, ERK, JNK, and Akt. Additionally, AD198 also potently inhibited the proliferation/survival and suppressed c-Myc expression in TRAF3-sufficient mouse and human B lymphoma cell lines. Furthermore, we found that reconstitution of c-Myc expression conferred partial resistance to the anti-proliferative/apoptosis-inducing effects of AD198 in human MM cells.
CONCLUSIONS: AD 198 and PEP005 have differential effects on malignant B cells through distinct biochemical mechanisms. Our findings uncovered a novel, PKCδ-independent mechanism of the anti-tumor effects of AD 198, and suggest that AD 198 has therapeutic potential for the treatment of NHL and MM involving TRAF3 inactivation or c-Myc up-regulation.

Choi J, Djebbar S, Fournier A, Labrie C
The co-chaperone DNAJC12 binds to Hsc70 and is upregulated by endoplasmic reticulum stress.
Cell Stress Chaperones. 2014; 19(3):439-46 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Human DNAJC12 is a J domain-containing protein whose regulation, subcellular localization, and function are currently unknown. We show here that the abundance of DNAJC12 in human LNCaP prostate cancer cells is upregulated by the stress-inducing drug A23187 and by the stressregulated transcription factor AIbZIP/CREB3L4. The DNAJC12 gene encodes two isoforms, only one of which (isoform a) is expressed in these cells. Immunofluorescence studies showed that a recombinant DNAJC12 protein is diffusely distributed in the cytoplasm. To identify substrates of DNAJC12, we used an immunoaffinity-mass spectrometry approach in cells that express epitope-tagged DNAJC12. The list of potential DNAJC12-binding proteins that were identified in this screen includes several nucleotide-binding proteins. The most frequently identified partner of DNAJC12 in unstressed cells was Hsc70, a cognate Hsp70 chaperone, whereas in stressed cells, the ER chaperone BiP was frequently associated with DNAJC12. Immunoprecipitation experiments confirmed that the endogenous DNAJC12 and Hsc70 proteins interact in LNCaP cells. These results clarify the role of DNAJC12 in the regulation of Hsp70 function.

Chanthammachat P, Promwikorn W, Pruegsanusak K, et al.
Comparative proteomic analysis of oral squamous cell carcinoma and adjacent non-tumour tissue from Thailand.
Arch Oral Biol. 2013; 58(11):1677-85 [PubMed] Related Publications
OBJECTIVE: The study was aimed at analysing and identifying the proteins that are differentially expressed in oral squamous cell carcinoma (OSCC) compared to adjacent non-tumour tissue.
MATERIALS AND METHODS: Two-dimensional (2D) sodium dodecyl sulphate-polyacrylamide gel electrophoresis accompanied by mass spectrometry (matrix-assisted laser desorption/ionisation-time-of-flight mass spectrometry and liquid chromatography-tandem mass spectrometry) was used to analyse and identify the differentially expressed proteins in 10 pairs of tumours and adjacent non-tumour tissues from five cases of early-stage and five cases of late-stage OSCC. The statistical differences of the protein spots were analysed by the Wilcoxon signed-rank test. A validation study using immunohistochemistry and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was performed.
RESULTS: A total of 68 proteins (63 up-regulated, five down-regulated) were differentially expressed in early-stage disease, and 39 proteins (37 up-regulated, two down-regulated) were significantly altered in late-stage disease. Among these, 14 proteins were altered in both groups. A total of 44 proteins were identified, including heat shock proteins (HSPs: Hsp90, HSPA5 and HSPA8), keratins (K1, K6A and K17), tubulin, cofilin 1, 14-3-3σ and metabolic enzymes. These proteins are involved in various cellular processes essential for cell growth, survival and cell migration. The validation study on α-tubulin and 14-3-3σ using immunohistochemistry and KIAA1199 expression using real-time RT-PCR confirmed the results in proteomics analysis.
CONCLUSIONS: The study identified many proteins, both known and unknown, for cancer cell processes. At least two proteins, KIAA1199 and Horf6, are novel for oral cancer.

Dadkhah E, Naseh H, Farshchian M, et al.
A cancer-array approach elucidates the immune escape mechanism and defects in the DNA repair system in esophageal squamous cell carcinoma.
Arch Iran Med. 2013; 16(8):463-70 [PubMed] Related Publications
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the second-most frequently diagnosed cancer in Northeast Iran, often diagnosed in advanced stages. No standard early diagnostic guideline has been proposed to date and current therapeutic modalities are not effective. Detection of tumor-specific biomarkers, which is the goal of this study, could prove useful in the diagnosis of ESCC. 
METHODS: To better understand the gene expression profile of ESCC, we analyzed tumor samples and corresponding adjacent normal tissues from ESCC patients by Chemiluminescent Human Cancer GEArrays. Candidate genes were verified by real-time PCR. 
RESULTS: Out of 440 cancer-related genes included in the array, 71 were overexpressed compared to normal tissue, with significant differences in 11 genes. There were 108 genes underexpressed, with significant differences in 5 genes. Until now, the AP2M1, FTL, UBE2L6, HLA-C, and HSPA8 overexpressed genes and XRCC5, TP53I3 and RAP1A underexpressed genes were not reported in ESCC. We chose the MMP2, HLA-G, and XRCC5 markers from 58 Iranian ESCC patients to verify the expression validity by real-time PCR. The microarray results were confirmed with two-tailed significance levels of P = 0.003 (MMP2), P = 0.000 (HLA-G) and P = 0.002(XRCC5). Analysis performed for the candidate genes using GNCpro online software highlighted two pathways, an immuno-modulatory response and DNA replication and repair. We successfully performed and validated Chemiluminescent GEArray gene expression profiling in ESCC. Several biomarkers that might be related to tumorigenesis in ESCC were identified.
CONCLUSION: Immuno-modulatory and DNA repair pathways could be used as targets to locate specific diagnostic, prognostic, and therapeutic biomarkers for ESCC.

Zhang L, Fok JJ, Mirabella F, et al.
Hsp70 inhibition induces myeloma cell death via the intracellular accumulation of immunoglobulin and the generation of proteotoxic stress.
Cancer Lett. 2013; 339(1):49-59 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Multiple myeloma (MM) cells rely on protein homeostatic mechanisms for survival. These mechanisms could be therapeutically targeted via modulation of the heat shock response. We studied the roles of Hsp72 and Hsc70, and show that the two major cytoplasmic Hsp70s play a key role in regulating protein homeostasis and controlling multiple oncogenic pathways in MM, and their inhibition can lead to myeloma cell death. Our study provides further evidence that targeting Hsp70 represents a novel therapeutic approach which may be effective in the treatment of MM.

Kao SH, Wang WL, Chen CY, et al.
GSK3β controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug.
Oncogene. 2014; 33(24):3172-82 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Glycogen synthase kinase 3 beta (GSK3β) is highly inactivated in epithelial cancers and is known to inhibit tumor migration and invasion. The zinc-finger-containing transcriptional repressor, Slug, represses E-cadherin transcription and enhances epithelial-mesenchymal transition (EMT). In this study, we find that the GSK3β-pSer9 level is associated with the expression of Slug in non-small cell lung cancer. GSK3β-mediated phosphorylation of Slug facilitates Slug protein turnover. Proteomic analysis reveals that the carboxyl terminus of Hsc70-interacting protein (CHIP) interacts with wild-type Slug (wtSlug). Knockdown of CHIP stabilizes the wtSlug protein and reduces Slug ubiquitylation and degradation. In contrast, nonphosphorylatable Slug-4SA is not degraded by CHIP. The accumulation of nondegradable Slug may further lead to the repression of E-cadherin expression and promote cancer cell migration, invasion and metastasis. Our findings provide evidence of a de novo GSK3β-CHIP-Slug pathway that may be involved in the progression of metastasis in lung cancer.

Kwon JY, Weon JI, Koedrith P, et al.
Identification of molecular candidates and interaction networks via integrative toxicogenomic analysis in a human cell line following low-dose exposure to the carcinogenic metals cadmium and nickel.
Oncol Rep. 2013; 30(3):1185-94 [PubMed] Related Publications
Cadmium and nickel have been classified as carcinogenic to humans by the World Health Organization's International Agency for Research on Cancer. Given their prevalence in the environment, the fact that cadmium and nickel may cause diseases including cancer even at low doses is a cause for concern. However, the exact mechanisms underlying the toxicological effects induced by low-dose exposure to cadmium and nickel remain to be elucidated. Furthermore, it has recently been recognized that integrative analysis of DNA, mRNA and proteins is required to discover biomarkers and signaling networks relevant to human toxicant exposure. In the present study, we examined the deleterious effects of chronic low-dose exposure of either cadmium or nickel on global profiling of DNA copy number variation, mRNA and proteins. Array comparative genomic hybridization, gene expression microarray and functional proteomics were conducted, and a bioinformatics tool, which predicted signaling pathways, was applied to integrate data for each heavy metal separately and together. We found distinctive signaling networks associated with subchronic low-dose exposure to cadmium and nickel, and identified pathways common to both. ACTB, HSP90AA1, HSPA5 and HSPA8, which are key mediators of pathways related to apoptosis, proliferation and neoplastic processes, were key mediators of the same pathways in low-dose nickel and cadmium exposure in particular. CASP-associated signaling pathways involving CASP3, CASP7 and CASP9 were observed in cadmium-exposed cells. We found that HSP90AA1, one of the main modulators, interacted with HIF1A, AR and BCL2 in nickel-exposed cells. Interestingly, we found that HSP90AA1 was involved in the BCL2-associated apoptotic pathway in the nickel-only data, whereas this gene interacted with several genes functioning in CASP-associated apoptotic signaling in the cadmium-only data. Additionally, JUN and FASN were main modulators in nickel-responsive signaling pathways. Our results provide valuable biomarkers and distinctive signaling networks that responded to subchronic low-dose exposure to cadmium and nickel.

Karim R, Tummers B, Meyers C, et al.
Human papillomavirus (HPV) upregulates the cellular deubiquitinase UCHL1 to suppress the keratinocyte's innate immune response.
PLoS Pathog. 2013; 9(5):e1003384 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Persistent infection of basal keratinocytes with high-risk human papillomavirus (hrHPV) may cause cancer. Keratinocytes are equipped with different pattern recognition receptors (PRRs) but hrHPV has developed ways to dampen their signals resulting in minimal inflammation and evasion of host immunity for sustained periods of time. To understand the mechanisms underlying hrHPV's capacity to evade immunity, we studied PRR signaling in non, newly, and persistently hrHPV-infected keratinocytes. We found that active infection with hrHPV hampered the relay of signals downstream of the PRRs to the nucleus, thereby affecting the production of type-I interferon and pro-inflammatory cytokines and chemokines. This suppression was shown to depend on hrHPV-induced expression of the cellular protein ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in keratinocytes. UCHL1 accomplished this by inhibiting tumor necrosis factor receptor-associated factor 3 (TRAF3) K63 poly-ubiquitination which lead to lower levels of TRAF3 bound to TANK-binding kinase 1 and a reduced phosphorylation of interferon regulatory factor 3. Furthermore, UCHL1 mediated the degradation of the NF-kappa-B essential modulator with as result the suppression of p65 phosphorylation and canonical NF-κB signaling. We conclude that hrHPV exploits the cellular protein UCHL1 to evade host innate immunity by suppressing PRR-induced keratinocyte-mediated production of interferons, cytokines and chemokines, which normally results in the attraction and activation of an adaptive immune response. This identifies UCHL1 as a negative regulator of PRR-induced immune responses and consequently its virus-increased expression as a strategy for hrHPV to persist.

Iżykowska K, Zawada M, Nowicka K, et al.
Identification of multiple complex rearrangements associated with deletions in the 6q23-27 region in Sézary syndrome.
J Invest Dermatol. 2013; 133(11):2617-25 [PubMed] Related Publications
The 6q23-27 region, recurrently deleted in Sézary syndrome (SS), was characterized at the molecular level in 13 SS patients and SS cell line SeAx. Using fine-tiling comparative genomic hybridization, deletions within the 6q23-27 region were detected in half of the samples (six patients and SeAx). All samples with deletions were further analyzed by ligation-mediated PCR. In addition, in one patient sample and in SeAx, paired-end next-generation sequencing was performed on the HiSeq2000 Illumina platform. Using those techniques, 23 rearrangements associated with the deletions were identified. The majority of rearrangements showed enormous complexity and diversity, including eight inversions, three transpositions, and four translocations (with chromosomes 3, 17, 10, and 12). Fifteen genes were disrupted by those rearrangements, the MYB proto-oncogene three times and the interleukin-22 receptor subunit alpha-2 gene (IL22RA2) twice. All three patients with MYB alterations showed low MYB expression, whereas seven of the remaining patients showed overexpression. Most patients overexpressing MYB also presented increased expression of MYC, HSPA8, and BCL2. Five gene fusions were identified, of which two, CCDC28A-IL22RA2 and AIG1-GOSR1, both in SeAx, were in the same orientation and were expressed at the messenger RNA level.

Yang X, Tian Z, Gou WF, et al.
Bag-3 expression is involved in pathogenesis and progression of colorectal carcinomas.
Histol Histopathol. 2013; 28(9):1147-56 [PubMed] Related Publications
Bcl-2-associated athanogene 3 (Bag-3) belongs to a member of the Hsc70 binding co-chaperone Bag-family proteins and has critical roles in protein homeostasis, cell survival, actin organization, cell adhesion, cell motility and tumor metastasis. To clarify the role of Bag-3 in colorectal carcinogenesis and subsequent development, its expression was examined by immunohistochemistry (IHC) and in situ hybridization (ISH) on tissue microarrays containing colorectal carcinomas, adenomas, non-neoplastic mucosa (NNM) and metastatic carcinomas in lymph node and liver. Colorectal carcinoma tissue and cell lines were studied for Bag-3 expression by RT-PCR, Western blot and immunofluorescence. The results demonstrated that Bag3 was distinctly expressed in Colo201, Colo205, DLD-1, HCT-15, HCT-116, HT-29, KM-12, SW480, SW620, and WiDr at both mRNA and protein levels. Carcinoma showed stronger Bag-3 expression than adjacent NNM by IHC and Western blot (P<0.05), while its mRNA had the opposite by real-time PCR and ISH (P<0.05). Metastatic carcinoma more frequently expressed Bag-3 mRNA in lymph node and liver than in primary carcinoma (P<0.05). Immunohistochemically, Bag-3 expression was seen to gradually decrease from carcinoma, adenoma to NNM (P<0.05). There was a positive correlation between Bag-3 expression and TNM staging and GRP94 expression (P<0.05), but no relationship to patient age or sex, tumor size, depth of invasion, lymphatic or venous invasion, lymph node metastasis, differentiation or prognosis of colorectal carcinomas (P<0.05). Our study indicated that aberrant Bag-3 expression might be involved in colorectal adenoma-adenocarcinoma sequence and subsequent progression.

Moghanibashi M, Rastgar Jazii F, Soheili ZS, et al.
Esophageal cancer alters the expression of nuclear pore complex binding protein Hsc70 and eIF5A-1.
Funct Integr Genomics. 2013; 13(2):253-60 [PubMed] Related Publications
Nuclear pore complex (NPC) is the only corridor for macromolecules exchange between nucleus and cytoplasm. NPC and its components, nucleoporins, play important role in the diverse physiological processes including macromolecule exchange, chromosome segregation, apoptosis and gene expression. Recent reports also suggest involvement of nucleoporins in carcinogenesis. Applying proteomics, we analyzed expression pattern of the NPC components in a newly established esophageal cancer cell line from Persia (Iran), the high-risk region for esophageal cancer. Our results indicate overexpression of Hsc70 and downregulation of subunit alpha type-3 of proteasome, calpain small subunit 1, and eIF5A-1. Among these proteins, Hsc70 and eIF5A-1 are in direct interaction with NPC and involved in the nucleocytoplasmic exchange. Hsc70 plays a critical role as a chaperone in the formation of a cargo-receptor complex in nucleocytoplasmic transport. On the other hand, it is an NPC-associated protein that binds to nucleoporins and contributes in recycling of the nucleocytoplasmic transport receptors in mammals and affects transport of proteins between nucleus and cytoplasm. The other nuclear pore interacting protein: eIF5A-1 binds to the several nucleoporins and participates in nucleocytoplasmic transport. Altered expression of Hsc70 and eIF5A-1 may cause defects in nucleocytoplasmic transport and play a role in esophageal carcinogenesis.

Razidlo GL, Wang Y, Chen J, et al.
Dynamin 2 potentiates invasive migration of pancreatic tumor cells through stabilization of the Rac1 GEF Vav1.
Dev Cell. 2013; 24(6):573-85 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
The large GTPase Dynamin 2 (Dyn2) is markedly upregulated in pancreatic cancer, is a potent activator of metastatic migration, and is required for Rac1-mediated formation of lamellipodia. Here we demonstrate an unexpected mechanism of Dyn2 action in these contexts via direct binding to the Rac1 guanine nucleotide exchange factor (GEF) Vav1. Surprisingly, disruption of the Dyn2-Vav1 interaction targets Vav1 to the lysosome for degradation via an interaction with the cytoplasmic chaperone Hsc70, resulting in a dramatic reduction of Vav1 protein stability. Importantly, a specific mutation in Vav1 near its Dyn2-binding C-terminal Src homology 3 (SH3) domain prevents Hsc70 binding, resulting in a stabilization of Vav1 levels. Dyn2 binding regulates the interaction of Vav1 with Hsc70 to control the stability and subsequent activity of this oncogenic GEF. These findings elucidate how Dyn2 activates Rac1, lamellipod protrusion, and invasive cellular migration and provide insight into how this specific Vav is ectopically expressed in pancreatic tumors.

Zhao D, Zou SW, Liu Y, et al.
Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer.
Cancer Cell. 2013; 23(4):464-76 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Tumor cells commonly have increased glucose uptake and lactate accumulation. Lactate is produced from pyruvate by lactate dehydrogenase A (LDH-A), which is frequently overexpressed in tumor cells and is important for cell growth. Elevated transcription by c-Myc or HIF1α may contribute to increased LDH-A in some cancer types. Here, we show that LDH-A is acetylated at lysine 5 (K5) and that this acetylation inhibits LDH-A activity. Furthermore, the K5-acetylated LDH-A is recognized by the HSC70 chaperone and delivered to lysosomes for degradation. Replacement of endogenous LDH-A with an acetylation mimetic mutant decreases cell proliferation and migration. Importantly, K5 acetylation of LDH-A is reduced in human pancreatic cancers. Our study reveals a mechanism of LDH-A upregulation in pancreatic cancers.

Mishra PB, Lobo AS, Joshi KS, et al.
Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma.
J Transl Med. 2013; 11:42 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
BACKGROUND: Tumors of the head and neck present aggressive pathological behavior in patients due to high expression of CDK/CCND1 proteins. P276-00, a novel CDK inhibitor currently being tested in clinic, inhibits growth of several cancers in vitro and in vivo. The pre clinical activity of P276-00 in head and neck cancer and its potential mechanisms of action at molecular level are the focus of the current studies.
METHOD: We have investigated the anti-cancer activity of P276-00 in head and neck tumors in vitro and in vivo. Candidate gene expression profiling and cell based proteomic approaches were taken to understand the pathways affected by P276-00 treatment.
RESULTS: It was observed that P276-00 is cytotoxic across various HNSCC cell lines with an IC₅₀ ranging from 1.0-1.5 μmoles/L and culminated in significant cell-cycle arrest in G1/S phase followed by apoptosis. P276-00 treatment suppressed cell proliferation through inhibition of CCND1 expression, reduced phosphorylation of retinoblastoma protein and abrogative transcription of E2F1 gene targets. Further, we observed that apoptosis was mediated through P53 activation leading to higher BAX/BCL-2 ratio and cleaved caspase-3 levels. It was also seen that P276-00 treatment reduced expression of tumor micro-environment proteins such as IL-6, secreted EGFR and HSPA8. Finally, P276-00 treatment resulted in significant tumor growth inhibition in xenograft tumor models via lowered proliferative activity of E2F1 and aggravated P53 mediated apoptosis.
CONCLUSION: In summary, we have observed that P276-00 inhibits cyclin-D/CDK4/P16/pRB/E2F axis and induces apoptosis by increased P53 phosphorylation in HNSCC cells. These results suggest a novel indication for P276-00 in head and neck cancer with a potential role for IL-6 and HSPA8 as candidate serum biomarkers.

Li L, Yang G, Ren C, et al.
Glioma pathogenesis-related protein 1 induces prostate cancer cell death through Hsc70-mediated suppression of AURKA and TPX2.
Mol Oncol. 2013; 7(3):484-96 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
In this study we report that expression of glioma pathogenesis-related protein 1 (GLIPR1) regulated numerous apoptotic, cell cycle, and spindle/centrosome assembly-related genes, including AURKA and TPX2, and induced apoptosis and/or mitotic catastrophe (MC) in prostate cancer (PCa) cells, including p53-mutated/deleted, androgen-insensitive metastatic PCa cells. Mechanistically, GLIPR1 interacts with heat shock cognate protein 70 (Hsc70); this interaction is associated with SP1 and c-Myb destabilization and suppression of SP1- and c-Myb-mediated AURKA and TPX2 transcription. Inhibition of AURKA and TPX2 using siRNA mimicked enforced GLIPR1 expression in the induction of apoptosis and MC. Recombinant GLIPR1-ΔTM protein inhibited AURKA and TPX2 expression, induced apoptosis and MC, and suppressed orthotopic xenograft tumor growth. Our results define a novel GLIPR1-regulated signaling pathway that controls apoptosis and/or mitotic catastrophe in PCa cells and establishes the potential of this pathway for targeted therapies.

Qiu Q, Hu B, Chen ZC, He XS
Sexual dimorphism of STGC3 tumor suppressor function in nasopharyngeal carcinoma CNE2 cells.
Genet Mol Res. 2012; 11(4):4585-97 [PubMed] Related Publications
STGC3 is a potential tumor suppressor in nasopharyngeal carcinoma. We previously found that CNE2 cells that re-expressed STGC3 formed smaller tumors in female mice than in male mice. Here, we investigated the sexual dimorphism of STGC3 as a tumor-suppressor in female and male nude mice injected subcutaneously with pcDNA3.1(+)-STGC3/CNE2 cells. ER-α was positively expressed in vitro in the CNE2 cells. The pcDNA3.1(+)-STGC3/CNE2 cell growth rate decreased after treatment with β-estradiol in vitro. There were significant differences in tumor size or mass between pcDNA3.1(+)-STGC3/CNE2 and control cases (P < 0.05), but there were significant differences in tumor size between female and male nude mice in the STGC3 transfection groups, and the pcDNA3.1(+)-STGC3/CNE2 tumor growth rate in the female nude mice was the lowest in all cases (P < 0.05). There were no significant differences between female and male nude mice in control groups. Furthermore, a greater number of cells were blocked in the G(0)/G(1) phase in pcDNA3.1(+)-STGC3/ CNE2 tumor xenografts in the female mice. Protemic analysis found 9 differentially expressed proteins in the pcDNA3.1-STGC3/CNE2 xenograft tissues in females and males. A heat shock 70 protein 8 isoform 2 variant was identified as a down-regulated protein associated with cell cycle control and its downstream factor cyclin D1 was also decreased in STGC3-repressed xenografts in female mice. The data above suggest that STGC3 and its associated proteins play an important role in nasopharyngeal carcinoma gender differences.

Chatterjee M, Andrulis M, Stühmer T, et al.
The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma.
Haematologica. 2013; 98(7):1132-41 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Despite therapeutic advances multiple myeloma remains largely incurable, and novel therapeutic concepts are needed. The Hsp90-chaperone is a reasonable therapeutic target, because it maintains oncogenic signaling of multiple deregulated pathways. However, in contrast to promising preclinical results, only limited clinical efficacy has been achieved through pharmacological Hsp90 inhibition. Because Hsp70 has been described to interact functionally with the Hsp90-complex, we analyzed the suitability of Hsp72 and Hsp73 as potential additional target sites. Expression of Hsp72 and Hsp73 in myeloma cells was analyzed by immunohistochemical staining and western blotting. Short interfering RNA-mediated knockdown or pharmacological inhibition of Hsp72 and Hsp73 was performed to evaluate the role of these proteins in myeloma cell survival and for Hsp90-chaperone function. Furthermore, the role of PI3K-dependent signaling in constitutive and inducible Hsp70 expression was investigated using short interfering RNA-mediated and pharmacological PI3K inhibition. Hsp72 and Hsp73 were frequently overexpressed in multiple myeloma. Knockdown of Hsp72 and/or Hsp73 or treatment with VER-155008 induced apoptosis of myeloma cells. Hsp72/Hsp73 inhibition decreased protein levels of Hsp90-chaperone clients affecting multiple oncogenic signaling pathways, and acted synergistically with the Hsp90 inhibitor NVP-AUY922 in the induction of death of myeloma cells. Inhibition of the PI3K/Akt/GSK3β pathway with short interfering RNA or PI103 decreased expression of the heat shock transcription factor 1 and down-regulated constitutive and inducible Hsp70 expression. Treatment of myeloma cells with a combination of NVP-AUY922 and PI103 resulted in additive to synergistic cytotoxicity. In conclusion, Hsp72 and Hsp73 sustain Hsp90-chaperone function and critically contribute to the survival of myeloma cells. Translation of Hsp70 inhibition into the clinic is therefore highly desirable. Treatment with PI3K inhibitors might represent an alternative therapeutic strategy to target Hsp70.

Zagouri F, Sergentanis TN, Gazouli M, et al.
HSP90, HSPA8, HIF-1 alpha and HSP70-2 polymorphisms in breast cancer: a case-control study.
Mol Biol Rep. 2012; 39(12):10873-9 [PubMed] Related Publications
This case control study aims to investigate the role of HSP90 Gln488His (C > G), HSP70-2 P1/P2, HIF-1 alpha C1772T and HSPA8 intronic 1541-1542delGT polymorphisms as potential risk factors and/or prognostic markers for breast cancer. 113 consecutive incident cases of histologically confirmed ductal breast cancer and 124 healthy cases were recruited. The above mentioned polymorphisms were genotyped; multivariate logistic regression was performed. HSP90 GG (His/His) genotype was associated with elevated breast cancer risk. Similarly, the allele dose-response model pointed to increase in breast cancer risk per G allele. HSP70-2 P1/P2, HSPA8 intronic 1541-1542delGT and HIF-1 alpha polymorphisms were not associated with breast cancer risk, as evidenced by the dose-response allele models. The positive association between HSP90 G allele and breast cancer risk seemed to pertain to both premenopausal and postmenopausal women. With respect to survival analysis, none of the aforementioned polymorphisms was associated with either disease-free survival or overall survival. HSP90α Gln488His polymorphism seems to be a risk factor for breast cancer. On the other hand, our study did not point to excess risk conferred by HSPA8 1541-1542delGT, Hsp70-2 P1/P2 and HIF-1α C1772T.

Liu T, Daniels CK, Cao S
Comprehensive review on the HSC70 functions, interactions with related molecules and involvement in clinical diseases and therapeutic potential.
Pharmacol Ther. 2012; 136(3):354-74 [PubMed] Related Publications
Heat shock cognate protein 70 (HSC70) is a constitutively expressed molecular chaperone which belongs to the heat shock protein 70 (HSP70) family. HSC70 shares some of the structural and functional similarity with HSP70. HSC70 also has different properties compared with HSP70 and other heat shock family members. HSC70 performs its full functions by the cooperation of co-chaperones. It interacts with many other molecules as well and regulates various cellular functions. It is also involved in various diseases and may become a biomarker for diagnosis and potential therapeutic targets for design, discovery, and development of novel drugs to treat various diseases. In this article, we provide a comprehensive review on HSC70 from the literatures including the basic general information such as classification, structure and cellular location, genetics and function, as well as its protein association and interaction with other proteins. In addition, we also discussed the relationship of HSC70 and related clinical diseases such as cancer, cardiovascular, neurological, hepatic and many other diseases and possible therapeutic potential and highlight the progress and prospects of research in this field. Understanding the functions of HSC70 and its interaction with other molecules will help us to reveal other novel properties of this protein. Scientists may be able to utilize this protein as a biomarker and therapeutic target to make significant advancement in scientific research and clinical setting in the future.

Cayado-Gutiérrez N, Moncalero VL, Rosales EM, et al.
Downregulation of Hsp27 (HSPB1) in MCF-7 human breast cancer cells induces upregulation of PTEN.
Cell Stress Chaperones. 2013; 18(2):243-9 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Hsp27 (HSPB1) is usually overexpressed in breast cancers affecting the disease outcome and the sensitivity of tumors to chemotherapy and radiotherapy. Hsp27 interacts with other proteins such as β-catenin, histone deacetylase HDAC6, transcription factor STAT2 and procaspase-3. Phosphatase and tensin homologue (PTEN) is a tumor suppressor gene that is deleted in many human tumors. The PI3K/Akt signaling pathway is negatively regulated by PTEN. Hsp27 is described as a key component of the Akt signaling cascade: Akt, BAD, Forkhead transcription factors, Hsp27, mitogen-activated protein kinase kinase-3 and -6. Here, we have examined whether the downregulation of Hsp27 by siHsp27 affects the PTEN levels in the MCF-7 human breast cancer cell line. PTEN was detected with two different antibodies using western blots and immunocytochemistry. p-Akt was also evaluated by western blot. In addition, Hsp27 and PTEN were immunoprecipitated to know whether these proteins interact. Intracellular colocalization studies were carried out by confocal microscopy. A significant reduction in the Hsp27 levels was noted in the siHsp27 transfected cells. These Hsp27 downregulated cells showed a significant increased expression of PTEN. The MW 76 and 55 kDa PTEN forms were upregulated as revealed by two different antibodies. The phosphatase activity of PTEN seems to be active because p-Akt levels were reduced. Hsp27 immunoprecipitation was bringing PTEN and vice versa, these two proteins seem to interact at cytoplasmic level by FRET. Downregulation of Hsp27 stabilized PTEN protein levels. Chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) levels were not significantly influenced by Hsp27 downregulation. In conclusion, we report a novel function of Hsp27 modulating the PTEN levels in human breast cancer cells suggesting an interaction between these two molecules.

Andreadi C, Cheung LK, Giblett S, et al.
The intermediate-activity (L597V)BRAF mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the RAF/MEK/ERK pathway.
Genes Dev. 2012; 26(17):1945-58 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
(L597V)BRAF mutations are acquired somatically in human cancer samples and are frequently coincident with RAS mutations. Germline (L597V)BRAF mutations are also found in several autosomal dominant developmental conditions known as RASopathies, raising the important question of how the same mutation can contribute to both pathologies. Using a conditional knock-in mouse model, we show that endogenous expression of (L597V)Braf leads to approximately twofold elevated Braf kinase activity and weak activation of the Mek/Erk pathway. This is associated with induction of RASopathy hallmarks including cardiac abnormalities and facial dysmorphia but is not sufficient for tumor formation. We combined (L597V)Braf with (G12D)Kras and found that (L597V)Braf modified (G12D)Kras oncogenesis such that fibroblast transformation and lung tumor development were more reminiscent of that driven by the high-activity (V600E)Braf mutant. Mek/Erk activation levels were comparable with those driven by (V600E)Braf in the double-mutant cells, and the gene expression signature was more similar to that induced by (V600E)Braf than (G12D)Kras. However, unlike (V600E)Braf, Mek/Erk pathway activation was mediated by both Craf and Braf, and ATP-competitive RAF inhibitors induced paradoxical Mek/Erk pathway activation. Our data show that weak activation of the Mek/Erk pathway underpins RASopathies, but in cancer, (L597V)Braf epistatically modifies the transforming effects of driver oncogenes.

Cheng L, Li J, Han Y, et al.
PES1 promotes breast cancer by differentially regulating ERα and ERβ.
J Clin Invest. 2012; 122(8):2857-70 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
The initiation of breast cancer is associated with increased expression of tumor-promoting estrogen receptor α (ERα) protein and decreased expression of tumor-suppressive ERβ protein. However, the mechanism underlying this process is unknown. Here we show that PES1 (also known as Pescadillo), an estrogen-inducible protein that is overexpressed in breast cancer, can regulate the balance between ERα and ERβ. We found that PES1 modulated many estrogen-responsive genes by enhancing the transcriptional activity of ERα while inhibiting transcriptional activity of ERβ. Consistent with this regulation of ERα and ERβ transcriptional activity, PES1 increased the stability of the ERα protein and decreased that of ERβ through the ubiquitin-proteasome pathway, mediated by the carboxyl terminus of Hsc70-interacting protein (CHIP). Moreover, PES1 transformed normal human mammary epithelial cells and was required for estrogen-induced breast tumor growth in nude mice. Further analysis of clinical samples showed that expression of PES1 correlated positively with ERα expression and negatively with ERβ expression and predicted good clinical outcome in breast cancer. Our data demonstrate that PES1 contributes to breast tumor growth through regulating the balance between ERα and ERβ and may be a better target for the development of drugs that selectively regulate ERα and ERβ activities.

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