Ha-rasval12 induces HSP70b transcription via the HSE/HSF1 system, but HSP70b expression is suppressed in Ha-rasval12-transformed cells

Stanhill, Ariel; Levin, V. L.; Hendel, Ayal; Shachar, Idit; Kazanov, Diana; Arber, Nadir; Kaminski, Naftali; Engelberg, David

doi:10.1038/sj.onc.1209193

Cited by 25 publications

(17 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1D). The present studies show that induction of AHA1 by 17-AAG is less extensive than is seen with HSP72, which contains four HSEs in its promoter (52). Nevertheless, despite the more limited response to 17-AAG compared with HSP72, the induction of the HSP90-activating protein AHA1 could potentially represent a protective mechanism for the cancer cell through the activation of HSP90 and potentially other unknown mechanisms.…”

Section: Discussionmentioning

confidence: 75%

Silencing of HSP90 Cochaperone AHA1 Expression Decreases Client Protein Activation and Increases Cellular Sensitivity to the HSP90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin

et al. 2008

View full text Add to dashboard Cite

AHA1 (activator of HSP90 ATPase) is a cochaperone of the ATP-dependent molecular chaperone, HSP90, which is involved in the maturation, stabilization/degradation, and function of oncogenic proteins. HSP90 operates in a multimeric complex driven by the binding and hydrolysis of ATP. Treatment of cells with the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) results in the degradation of client proteins via the ubiquitin-proteasome pathway. As AHA1 increases the ATPase activity of HSP90, we hypothesized that modulation of AHA1 expression could influence the activity of client proteins and/or the cellular response to 17-AAG. We show that the basal expression of AHA1 is different across a panel of human cancer cell lines, and that treatment with 17-AAG resulted in sustained AHA1 up-regulation. Increasing the expression of AHA1 did not affect the sensitivity to 17-AAG, but did increase C-RAF activity and the levels of phosphorylated MEK1/2 and ERK1/2 without affecting total levels of these proteins or of client proteins C-RAF, ERBB2, or CDK4. Conversely, small interfering RNA-selective knockdown of >80% of AHA1 expression decreased C-RAF activity and reduced the levels of MEK1/2 and ERK1/2 phosphorylation. Moreover, the AHA1 knockdown resulted in a significant (P < 0.05) increase in sensitivity to 17-AAG, due in part to a 2-to 3-fold increase in apoptosis. These results show that the reduction of AHA1 levels could decrease the phosphorylation of key signal transduction proteins, and for the first time, separate the activation and stabilization functions of HSP90. Furthermore, AHA1 knockdown could sensitize cancer cells to 17-AAG. We conclude that modulation of AHA1 might be a potential therapeutic strategy to increase sensitivity to HSP90 inhibitors. [Cancer Res 2008;68(4):1187-96]

show abstract

Section: Discussionmentioning

confidence: 75%

Silencing of HSP90 Cochaperone AHA1 Expression Decreases Client Protein Activation and Increases Cellular Sensitivity to the HSP90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin

et al. 2008

View full text Add to dashboard Cite

show abstract

“…The stimulus most widely assigned to drive HSF1 activation in cancer is increased substrate burden on the heat shock protein/chaperone machinery. Dysregulation of the protein translation machinery (53), imbalanced protein production due to aneuploidy (54,55), and accumulation of mutated, highly chaperone-dependent oncoproteins all strain the chaperone machinery (56)(57)(58). Support for this model of HSF1 activation comes from observations that the HSP90-based chaperone machinery may be pressed to operate at its maximal capacity in cancer cells (59), thereby releasing HSF1 from a repressive complex with HSP90 (60).…”

Section: Hsf1 Supports Mapk/erk Signaling In Nf1-deficient Cellsmentioning

confidence: 85%

Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis

Dai

Santagata²,

Tang³

et al. 2012

J. Clin. Invest.

123

151

View full text Add to dashboard Cite

Intrinsic stress response pathways are frequently mobilized within tumor cells. The mediators of these adaptive mechanisms and how they contribute to carcinogenesis remain poorly understood. A striking example is heat shock factor 1 (HSF1), master transcriptional regulator of the heat shock response. Surprisingly, we found that loss of the tumor suppressor gene neurofibromatosis type 1 (Nf1) increased HSF1 levels and triggered its activation in mouse embryonic fibroblasts. As a consequence, Nf1 -/-cells acquired tolerance to proteotoxic stress. This activation of HSF1 depended on dysregulated MAPK signaling. HSF1, in turn, supported MAPK signaling. In mice, Hsf1 deficiency impeded NF1-associated carcinogenesis by attenuating oncogenic RAS/MAPK signaling. In cell lines from human malignant peripheral nerve sheath tumors (MPNSTs) driven by NF1 loss, HSF1 was overexpressed and activated, which was required for tumor cell viability. In surgical resections of human MPNSTs, HSF1 was overexpressed, translocated to the nucleus, and phosphorylated. These findings reveal a surprising biological consequence of NF1 deficiency: activation of HSF1 and ensuing addiction to this master regulator of the heat shock response. The loss of NF1 function engages an evolutionarily conserved cellular survival mechanism that ultimately impairs survival of the whole organism by facilitating carcinogenesis. IntroductionEvolutionarily conserved from yeasts to humans, the heat shock transcription factor heat shock factor 1 (HSF1) is activated by a broad range of stressors that extend far beyond heat, including heavy metals, UV radiation, hypoxia, desiccation, and acidosis (1). During activation, HSF1 undergoes phosphorylation and other posttranslational modifications, trimerization, and nuclear translocation. This results in rapid, high-affinity binding of HSF1 to consensus heat shock elements (HSEs) within the promoters of target genes (2). Such binding drives the induction or suppression of hundreds of genes in mammalian cells (3).The adaptive response unleashed by HSF1 activation is critical for maintaining homeostasis of the cell's proteome, mediated in large part by increased expression of classical heat shock proteins such as HSP27, HSP70, and HSP90 (4). However, the effect of HSF1 activation goes far beyond these chaperones. It helps coordinate a range of fundamental cellular processes that are important to the fitness of malignant cells, including cell cycle control, ribosome biogenesis, protein translation, and glucose metabolism (5, 6). As a result, HSF1 both facilitates initial oncogenic transformation and maintains the malignant phenotype of established cancer cell lines driven by a wide range of mutations. In mice and in cell culture, genetic ablation of Hsf1 expression potently impairs tumorigenesis and cellular transformation driven by oncogene activation or tumor suppressor loss (5). The importance of HSF1 in enabling malignancy has been demonstrated by other recent work as well

show abstract

“…Reverse Transcription-PCR-Total RNA was extracted as described (50). DNA was digested by Turbo DNase (Ambion) and RNA (2 g) was subjected to reverse transcription using the murine leukemia virus reverse transcriptase (Roche Applied Science), with random hexamers as primers.…”

Section: Methodsmentioning

confidence: 99%

Hyperactive Variants of p38α Induce, whereas Hyperactive Variants of p38γ Suppress, Activating Protein 1-mediated Transcription

Askari

Diskin

Avitzour

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The p38 family of kinases is a subgroup of the mitogen-activated protein kinase family. It is composed of four isoforms and is involved in critical biological processes as well as in inflammatory diseases. The exact unique role of each p38 isoform in these processes is not understood well. To approach this question we have been developing intrinsically active variants of p38s. Recently we described a series of mutants of the human p38␣, which were spontaneously active as recombinant proteins purified from Escherichia coli cells. We show here that some of these mutants are spontaneously active in several mammalian cells in culture. The spontaneous activity of some mutants is higher than the activity of the fully activated wild type counterpart. We further produced mutants of the other p38 isoforms and found that p38␤ D176A , p38␥ D179A , p38␦ D176A , and p38␦ F324S are spontaneously active in vivo. The active mutants are also spontaneously phosphorylated. To test whether the mutants actually fulfill downstream duties of p38 proteins, we tested their effect on activating protein 1(AP-1)-mediated transcription. Active mutants of p38␣ induced AP-1-driven reporter genes, as well as the c-jun and c-fos promoters. An active variant of p38␥ suppressed AP-1-mediated transcription. When active variants of p38␣ and p38␥ were co-expressed, AP-1 activity was not induced, showing that p38␥ is dominant over p38␣ with respect to AP-1 activation. Thus, intrinsically active variants that are spontaneously active in vivo have been obtained for all p38 isoforms. These variants have disclosed different effects of each isoform on AP-1 activity.

show abstract

Ha-rasval12 induces HSP70b transcription via the HSE/HSF1 system, but HSP70b expression is suppressed in Ha-rasval12-transformed cells

Cited by 25 publications

References 81 publications

Silencing of HSP90 Cochaperone AHA1 Expression Decreases Client Protein Activation and Increases Cellular Sensitivity to the HSP90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin

Silencing of HSP90 Cochaperone AHA1 Expression Decreases Client Protein Activation and Increases Cellular Sensitivity to the HSP90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin

Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis

Hyperactive Variants of p38α Induce, whereas Hyperactive Variants of p38γ Suppress, Activating Protein 1-mediated Transcription

Contact Info

Product

Resources

About