A gain-of-function mutant p53–HSF1 feed forward circuit governs adaptation of cancer cells to proteotoxic stress

Li, D; Yallowitz, Alisha R.; Ozog, Lukasz S.; Marchenko, Natalia D.

doi:10.1038/cddis.2014.158

Cited by 84 publications

(107 citation statements)

References 37 publications

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Section: Resultssupporting

confidence: 91%

“…Consistent with our current in vivo data, we recently showed in vitro that RNAi mediated downregulation of mutp53 in ErbB2 positive SKBR3 human breast cancer cells promotes ErbB2 degradation 32 . Conversely, ectopic overexpression of the R175H p53 mutant increases ErbB2 levels in SKBR3 cells 32 . Hence, mutp53, via amplification of ErbB2 signaling, may promote the expansion of the SC pool, leading to increased metastatic recurrence, as observed in mutp53/HER2 -positive breast cancer patients 5 .…”

Section: Resultssupporting

confidence: 91%

“…Sustained activation of EGFR can play important role for high self-renewal potential, survival, invasion and metastases of cancer stem/progenitor cells and their progenies 18 . Previous our and others data revealed mutp53 can enhance EGFR signaling by increasing its recycling efficiency 34 and/or stability 32 .…”

Section: Resultsmentioning

confidence: 54%

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Mutant p53 Amplifies Epidermal Growth Factor Receptor Family Signaling to Promote Mammary Tumorigenesis

Yallowitz

Lobko

et al. 2015

Molecular Cancer Research

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The epidermal growth factor receptor family (ErbB2/Her2 and EGFR/ErbB1/Her1) often modulates the transcriptional program involved in promoting mammary tumorigenesis. In humans, more than 70% of ErbB2-positive sporadic breast cancers harbor p53 mutations, which correlate with poor prognosis. Also, the extremely high incidence of ErbB2-positive breast cancer in women with p53 germ-line mutations (Li-Fraumeni Syndrome) suggests the key role of mutant p53 specifically in ErbB2-mediated mammary tumorigenesis. To examine the role of mutant p53 during ErbB2-mediated mammary tumorigenesis we introduced a mutant p53 R172H allele into a (MMTV)-ErbB2/Neu mouse model. We show in heterozygous p53 mice that mutp53 R172H is a more potent activator of ErbB2-mediated mammary tumorigenesis than simple loss of p53. The more aggressive disease in mutant p53 animals was reflected by earlier tumor onset, increased mammary tumor multiplicity, and shorter survival. We provide molecular evidence that mutant p53 amplifies ErbB2 and EGFR signaling to promote the expansion of mammary stem cells and induce cancer cell proliferation. This study therefore identifies mutant p53 as an essential player in ErbB2 and EGFR-mediated breast cancer and indicates the potential translational importance of targeting mutant p53 in this subset of breast cancer patients.

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Section: Resultssupporting

confidence: 91%

Section: Resultssupporting

confidence: 91%

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Mutant p53 Amplifies Epidermal Growth Factor Receptor Family Signaling to Promote Mammary Tumorigenesis

Yallowitz

Lobko

et al. 2015

Molecular Cancer Research

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“…It has been reported that mut p53 positively regulates HSF1 levels and activity [23]. We also confirmed that the level of HSF1 was decreased in amurensin G-treated MCF7-MDR cells transfected with control siRNA but not CHIP knock-downed cells.…”

Section: Chip-mediated Mut P53 Degradation Leads To Downregulation Ofsupporting

confidence: 76%

SIRT1 Inhibitor Enhances Hsp90 Inhibitor-mediated Abrogation of Hsp90 Chaperone Function and Potentiates the Cytotoxicity of Hsp90 Inhibitor in Chemo-resistant Human Cancer Cells

Moon¹,

Lee²,

Kim³

et al. 2016

Journal of Life Science

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The present investigation was undertaken to examine the effectiveness of the combination treatment of an Hsp90 inhibitor and a SIRT1 inhibitor on suppressing the growth of chemo-resistant human cancer cells. We showed that inhibition of SIRT1 effectively potentiated the cytotoxicity of 17-allylamino-17-demethoxygeldanamycin (17-AAG) and reversed Hsp90 inhibitor resistance in multidrug-resistant (MDR) human ovarian HeyA8-MDR cells. Amurensin G, a potent natural SIRT1 inhibitor, enhanced Hsp90 inhibitor-mediated abrogation of the Hsp90 chaperone function and accelerated degradation of mutated p53 (mut p53), an Hsp90 client protein, by up-regulation of ubiquitin ligase CHIP. Knockdown of CHIP significantly attenuated amurensin G-induced mut p53 degradation. Down-regulation of mut p53 reduced the expression of heat shock factor1 (HSF1)/heat shock proteins (Hsps), a major cause of Hsp90 inhibitor resistance, which led to sensitization of the MDR cells to the Hsp90 inhibitor by the SIRT1 inhibitor. Amurensin G potentiated cytotoxicity of the Hsp90 inhibitor in HeyA8-MDR cells through suppression of 17-AAG-induced Hsp70 and Hsp27 induction via down-regulation of mut p53/HSF1, and it caused activation of PARP and inhibition of Bcl-2. Our data suggests that SIRT1 inhibitors could be used to sensitize MDR cells to Hsp90 inhibitors, possibly through suppression of the mut p53/HSF1-dependent pathway, and a novel mut p53-directed action of SIRT1 inhibition could effectively prevent mut p53 accumulation in MDR cells.

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“…Similar findings with respect to stabilization of Hsp90 client proteins by Her2/HSF1 axis came from a study where inhibition of Her2 signaling resulted in the inhibition of HSF1 activity (phosphorylation) and the destabilization of HSP90 clients including MIF (macrophage migration inhibitory factor) and AKT (17). Recent studies have demonstrated that overexpression of mutant p53 also activates EGFR/Her2, leading to enhanced PI3K and MAPK signaling, which results in the phosphorylation and activation of HSF1 (32). These studies suggest that HSF1-dependent chaperoning of Hsp90 client proteins is dependent on growth factor (growth factor-PI3K-AKT) signaling.…”

Section: Ras-mapk and Mutant P53 Signaling In Tumorssupporting

confidence: 54%

Heat Shock Factor 1 in Protein Homeostasis and Oncogenic Signal Integration

2015

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Heat shock factor 1 (HSF1) is a stress-inducible transcription factor and has been described as a multi-faceted modulator of tumorigenesis. Heat shock, accumulation of misfolded proteins, or malignant transformation promotes the activation and nuclear translocation of HSF1, where it binds to the promoters of heat shock proteins and an array of nonheat shock-regulated proteins to upregulate their transcription. These stress-responsive and tumor-promoting genes in turn alter the ability of tumor cells to respond to a variety of stresses and enable them to thrive in less than favorable growth conditions. Although a direct role for HSF1 in promoting mRNA transcription of tumor-promoting genes has been suggested, it appears that this property is context-and celltype dependent. Furthermore, recent studies have demonstrated a direct involvement of mTOR signaling in regulating HSF1-mediated transcription, thus establishing a direct link between protein translation and HSF1 activity. Interestingly, there is a growing understanding of the signaling pathways that are modulated by HSF1 in a variety of tumor types and the co-option of these survival pathways by HSF1 to promote tumorigenesis. This review will focus on the role of HSF1 in protein homeostasis and HSF1-mediated oncogenic signaling pathways that together promote tumorigenesis. Cancer Res; 75(6); 907-12. Ó2015 AACR.

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A gain-of-function mutant p53–HSF1 feed forward circuit governs adaptation of cancer cells to proteotoxic stress

Cited by 84 publications

References 37 publications

Mutant p53 Amplifies Epidermal Growth Factor Receptor Family Signaling to Promote Mammary Tumorigenesis

Mutant p53 Amplifies Epidermal Growth Factor Receptor Family Signaling to Promote Mammary Tumorigenesis

SIRT1 Inhibitor Enhances Hsp90 Inhibitor-mediated Abrogation of Hsp90 Chaperone Function and Potentiates the Cytotoxicity of Hsp90 Inhibitor in Chemo-resistant Human Cancer Cells

Heat Shock Factor 1 in Protein Homeostasis and Oncogenic Signal Integration

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