High Levels of Heat Shock Protein Hsp72 in Cancer Cells Suppress Default Senescence Pathways

Yaglom, Julia A.; Gabai, Vladimir L.; Sherman, Michael Y.

doi:10.1158/0008-5472.can-06-3796

Cited by 103 publications

(114 citation statements)

References 35 publications

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“…In fact, g-IR of control cells led to about twofold stabilization of p53, resulting in the halflife B50 min, whereas about fourfold stabilization of p53 was observed on g-IR of shHsp72 cells, where the half-life of p53 became longer than 3 h (Figure 5e). (Of note, as reported earlier, depletion of Hsp72 on its own led to a moderate stabilization of p53; Yaglom et al, 2007).…”

Section: Suppression Of Ch2ax By Hsp72 Depletionsupporting

confidence: 83%

“…shRNA retrovirus-mediated depletion of Hsp72 in HeLa cells (Figure 1a; Yaglom et al, 2007) also resulted in strong suppression of H2AX phosphorylation following UVC irradiation and CPT treatment (Figure 1c,top panel). Similarly, suppression of H2AX phosphorylation was also observed when shHsp72-HCT116 or HeLa cells were subjected to g-IR or Dox (Figures 1b and c).…”

Section: Downregulation Of Hsp72 Impairs Phosphorylation Of H2ax On Vmentioning

confidence: 94%

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HSP72 depletion suppresses γH2AX activation by genotoxic stresses via p53/p21 signaling

2010

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Section: Suppression Of Ch2ax By Hsp72 Depletionsupporting

confidence: 83%

Section: Downregulation Of Hsp72 Impairs Phosphorylation Of H2ax On Vmentioning

confidence: 94%

HSP72 depletion suppresses γH2AX activation by genotoxic stresses via p53/p21 signaling

2010

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“…HSP70 membrane positivity correlated with better prognosis in cancers which metastasize to the liver where natural killer cells exist in abundance, but worse prognosis was noted in cancers that are not exposed to natural killer surveillance. It can thus be inferred that high expression of HSP70 in cells is beneficial for the cancer cell survival due to intracellular cancer promoting effects of HSP70 (Ciocca and Calderwood 2005;Schmitt et al 2007;Yaglom et al 2007) unless immune surveillance has a role in the control of the particular cancer where HSP70 membrane positivity acts as a danger signal for natural killer cells (Multhoff et al 1999;Wallin et al 2002;Gehrmann et al 2005). The association we report here between high-expression-associated HSPA1B genotype and protection from childhood ALL therefore suggests the involvement of immune surveillance in the development of ALL.…”

Section: Discussionmentioning

confidence: 70%

HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility

Ucisik-Akkaya

Davis

Gorodezky

et al. 2010

Cell Stress and Chaperones

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Three heat shock protein 70 (HSP70) genes, HSPA1L, HSPA1A, and HSPA1B, are located within the human leukocyte antigen (HLA) class III region. HSPs act as stress signals and regulate natural killer cell response to cancer. HSP70 gene polymorphisms show disease associations partly due to their linkage disequilibrium with HLA alleles. To systematically evaluate their associations with childhood acute lymphoblastic leukemia (ALL), we examined the three functional single nucleotide polymorphisms (SNPs) rs2227956 (T493M) in HSPA1L, rs1043618 in HSPA1A 5′UTR, and rs1061581 (Q351Q) in HSPA1B by TaqMan assays or polymerase chain reaction-restriction fragment length polymorphism in 114 ALL cases and 414 controls from Wales (UK), in 100 Mexican Mestizo ALL cases and 253 controls belonging to the same ethnic group, and in a panel of 82 HLA-typed reference cell line samples. Homozygosity for HSPA1B rs1061581 minor allele G was associated with protection (odds ratio (OR)=0.37, 95% confidence interval (CI)=0.16-0.78; P=0.007) with genedosage effect (additive model) reaching significance (P= 0.0001) in the Welsh case-control group. This association was replicated in the second case-control group from Mexico (OR (recessive model)=0.49, 95% CI=0.24-0.96; P=0.03), and the pooled analysis yielded a strong association (Mantel-Haenszel OR=0.43, 95% CI=0.27-0.69, P= 0.0004). The association was stronger in males in each group and in the pooled analysis. A three-SNP haplotype including the major allele A of rs1061581 showed a highly significant increase in Welsh cases compared with respective controls (6.7% vs 1.8%; P=0.0003) due to the difference between male cases and controls. The protective allele of rs1061581 occurred more frequently on the HLA-DRB3 haplotypes (especially DRB1*03) in the cell line panel, but the HSPA1B association was independent from the HLA-DRB4 association previously detected in the same case-control group from Wales (adjusted P=0.001). Given the cancer promoting roles played by HSPs intracellularly as well as roles in immune surveillance when expressed on the cell surface and the known correlations between expression levels and the HSP polymorphisms, these results are likely to indicate a primary association and warrant detailed assessment in childhood ALL development.

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“…Recently, HSP72 was shown to be upregulated in some chronic diseases. [25][26][27] Our recent study, as well as reports by others, showed that HSP72 suppresses EMT and fibrosis, 10,28 -30 critical processes that promote chronic renal injury.…”

Section: Discussionmentioning

confidence: 99%

HSP72 Inhibits Smad3 Activation and Nuclear Translocation in Renal Epithelial-to-Mesenchymal Transition

Zhou¹,

Mao²,

Li³

et al. 2010

Journal of the American Society of Nephrology

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Although heat shock protein 72 (HSP72) ameliorates renal tubulointerstitial fibrosis by inhibiting epithelial-to-mesenchymal transition (EMT), the underlying mechanism is unknown. Because Smad proteins transduce TGF-␤ signaling from the cytosol to the nucleus and HSP72 assists in protein folding and facilitates nuclear translocation, we investigated whether HSP72 inhibits TGF-␤-induced EMT by modulating Smad expression, activation, and nuclear translocation. To evaluate the roles of distinct HSP72 structural domains in these processes, we constructed vectors that expressed wild-type HSP72 or mutants lacking either the peptide-binding domain (HSP72-⌬PBD), which is responsible for substrate binding and refolding, or the nuclear localization signal (HSP72-⌬NLS). Overexpression of wild-type HSP72 or HSP72-⌬NLS inhibited TGF-␤1-induced EMT, but HSP72-⌬PBD did not, suggesting a critical role for the PBD in this inhibition. HSP72 overexpression inhibited TGF-␤1-induced phosphorylation and nuclear translocation of Smad3 and p-Smad3, but not Smad2; these inhibitory effects required the PBD but not the NLS. Coimmunoprecipitation assays suggested a physical interaction between Smad3 and the PBD. siRNA knockdown of endogenous HSP72 enhanced both TGF-␤1-induced Smad3 phosphorylation and EMT and confirmed the interaction of HSP72 with both Smad3 and p-Smad3. In vivo, induction of HSP72 by geranylgeranylacetone suppressed Smad3 phosphorylation in renal tubular cells after unilateral ureteral obstruction. In conclusion, HSP72 inhibits EMT in renal epithelial cells primarily by exerting domain-specific effects on Smad3 activation and nuclear translocation. 21: 598 -609, 201021: 598 -609, . doi: 10.1681 Transforming growth factor ␤ (TGF-␤) and related factors regulate a wide variety of biologic activities. 1 Furthermore, abnormalities in TGF-␤ signaling lead to various human diseases. 2 Signals from TGF-␤ are mainly transduced by the Smad family of transcription factors. Upon TGF-␤ stimulation, Smad2 and Smad3 are phosphorylated at their carboxy-tails by the activated TGF-␤ type I receptor kinase, 3 forming a stable complex with Smad4 in cytoplasm and then accumulating in the nucleus to regulate transcription of target genes. In contrast, Smad7 inhibits the TGF-␤ receptor type I-dependent Smad2/3 activation. It has been demonstrated that Smad3 phosphorylation plays a predominant role in guiding the complex through the nuclear pore. 4 cytoplasm. 5 Blockade of TGF-␤ signaling events, specifically the phosphorylation of Smad2 and Smad3 and/or nuclear translocation, prevent epithelial-to-mesenchymal transition (EMT) and tissue fibrosis. 6,7 Heat shock protein 72 (HSP72) exerts cytoprotective effects by assisting in protein folding, assembly/disassembly and translocation of client proteins across membranes, protein degradation, and signal transduction. 8,9 However, some cytoprotective effects do not require the HSP72 chaperone function. 10 HSP72 contains distinct domains: a C-terminal peptide-binding domain (PBD) responsible...

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High Levels of Heat Shock Protein Hsp72 in Cancer Cells Suppress Default Senescence Pathways

Cited by 103 publications

References 35 publications

HSP72 depletion suppresses γH2AX activation by genotoxic stresses via p53/p21 signaling

HSP72 depletion suppresses γH2AX activation by genotoxic stresses via p53/p21 signaling

HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility

HSP72 Inhibits Smad3 Activation and Nuclear Translocation in Renal Epithelial-to-Mesenchymal Transition

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