Role of HSP90, CDC37, and CRM1 as modulators of P16<sup>INK4A</sup>activity in rat liver carcinogenesis and human liver cancer

Pascale, Rosa M.; Simile, Maria M.; Calvisi, Diego F.; Frau, Maddalena; Muroni, Maria Rosaria; Seddaiu, Maria A.; Daino, Lucia; Muntoni, Maria Donatella; Miglio, Maria Rosaria De; Thorgeirsson, Snorri S.; Feo, Francesco

doi:10.1002/hep.20962

Cited by 88 publications

(137 citation statements)

References 39 publications

(51 reference statements)

Supporting

Mentioning

125

Contrasting

Order By: Relevance

“…This association with growth and replication also applies to a tumor suppressor gene, LATS1 [89], and the insulin-like growth factor 1 receptor [90]. The expression of one of these genes, CDC37, is mediated by the gene HSP90 [91], which is intimately involved in carcinogenesis [92] and has evolved under positive selection in some mammals [93].…”

Section: Mta1mentioning

confidence: 97%

The androgen receptor and prostate cancer: A role for sexual selection and sexual conflict?

Summers

Crespi

2008

Medical Hypotheses

View full text Add to dashboard Cite

Summary We propose and evaluate the hypothesis that the CAG repeat region of the androgen receptor represents a locus of antagonistic pleiotropy in the context of sexual selection and sexual conflict. Short repeats are associated with increased transactivation of the androgen receptor at the molecular level, and increased fertility at the phenotypic level. However, short repeats are also associated with increased risk of prostate cancer, and with more aggressive forms of the disease. The somatic evolution of cancer cell lineages also shows a repeated pattern of shortening of the CAG repeat in association with cancer progression, apparently as a result of positive selection among cell lineages. We further postulate that other genes associated with prostate cancer are likely to mediate antagonistic pleiotropy in the context of sexual selection and sexual conflict. A key prediction of this hypothesis is that the genes mediating antagonistic pleiotropy will show historical evidence of positive selection, particularly in the context of sexual conflict. Previous research on the molecular evolution of specific genes associated with prostate cancer supports this prediction, and we suggest further critical tests of the role for genomic conflicts and tradeoffs in the evolution of cancer risk.

show abstract

Section: Mta1mentioning

confidence: 97%

The androgen receptor and prostate cancer: A role for sexual selection and sexual conflict?

Summers

Crespi

2008

Medical Hypotheses

View full text Add to dashboard Cite

show abstract

“…kinases required for proliferation or perhaps for repeated rounds of kinase re-activation 9,12,13 . For instance, increased levels of Cdc37 in vivo correlate with the upregulation of the G 1 -specific cyclin D1 in proliferating normal tissues 3 .…”

mentioning

confidence: 99%

Targeting the oncogene and kinome chaperone CDC37

et al. 2008

View full text Add to dashboard Cite

Cdc37 is a molecular chaperone that physically stabilizes the catalytic domains found in protein kinases and is therefore a wide-spectrum regulator of protein phosphorylation. It is also an overexpressed oncogene that mediates carcinogenesis by stabilizing the compromised structures of mutant and/or overexpressed oncogenic kinases. Recent work shows that such dependency of malignant cells on elevated Cdc37 expression is a vulnerability that can be targeted in cancer by agents that deplete or inhibit Cdc37. Cdc37 is thus a candidate for broad-spectrum molecular cancer therapy.Although Cdc37 is overexpressed in a number of cancers, it is an unusual oncoprotein whose transforming character does not readily snap into place in the conventional oncogenic pathways. Instead, it is a molecular chaperone, a protein that facilitates folding/refolding of other proteins, often described as its "clients". The role of molecular chaperones in cancer was first characterized with regard to Hsp90 (for review see 5 ). Hsp90 is a facilitator of oncogenesis that stabilizes a wide range of overexpressed or mutated oncogenic proteins and permits their tumorigenic influence to arise 3,7 . Tumors thus appear to become addicted to chaperones and can be treated by withdrawing the chaperoning power of Hsp90 [4][5][6] . Cdc37 interacts with a subset of client proteins within Hsp90 complexes and plays a specialized role as primary partner in kinome maintenance 3,8,9 . This specialized property of Cdc37 fuels the acceleration of cell proliferation observed in cancer by promoting the activities of a broad array of protein kinases 1-3 . These include receptor tyrosine kinases such as EGFR and MET, non-receptor tyrosine kinases v-src and Lck, and intracellular serine/threonine kinases Raf-1, Ksr, Akt, IKK, Cdc2, Cdk2 and Cdk4. A comprehensive list of Cdc37 client kinases, including the ones listed above and others can be found at the website of Dr Didier Picard: http://www.picard.ch/downloads/Cdc37interactors.pdf. The degree of dependency of the cancer cell kinome on Cdc37 expression thus appears to be extensive and in a recent yeast screen, at least 90 % of the protein kinases examined required Cdc37 for function 10 .The defining cellular role for Cdc37, which becomes misappropriated in cancer, resides in its promotion of cell proliferation. Indeed this protein was first discovered in a yeast screen for cell division cycle proteins, hence its name 11 . Thus when mammalian tissues undergo rapid proliferation during development, the normally scarce levels of Cdc37 are rapidly expanded. Elevated levels of Hsp90/Cdc37 complexes mediate the maturation and stabilization of protein 3Correspondence to: Stuart K. Calderwood, 21-27 Burlington Ave. Rm. 553B, Boston, MA 02215, scalderw@bidmc.harvard.edu. 2 Current address: Johns Hopkins University School of Medicine, Baltimore, MD 21205Because of space limitations we were unable to cite many significant studies on Cdc37 and Hsp90. We apologize to the authors of such studies and refer to excellent pu...

show abstract

“…Consequently, the increase in Cdc37-Cdk4 complex resulted in a decrease in p16 INK4A -Cdk4 complex in the lesions of F344 rats, whereas lower/no changes occurred in BN rats [61] . The transcription factor E2f4, is a p16 INK4A effector, acting as a growth repressor [65] , equally expressed in the lesions of both F344 and BN rats.…”

Section: Cell Cycle Deregulationmentioning

confidence: 89%

“…In contrast, only very few preneoplastic lesions of resistant BN rats grow autonomously after the end of the promoting stage; the majority of lesions remodel or no further evolve to neoplasia [61] . To evaluate the molecular mechanisms underlying the appearance of the resistant phenotype in BN rats [61] , the behavior of the p16 INK4A and some genes regulating cell cycle inhibition by p16…”

Section: Cell Cycle Deregulationmentioning

confidence: 90%

“…Au t o n o m o u s l y g r ow i n g p r e n e o p l a s t i c l ive r nodules develop in susceptible rat strains, initiated by diethylnitrosamine and subjected to the initiation/ selection treatments of the "resistant hepatocyte" protocol, after the cessation (about 6 wk after initiation) of the promotion stimulus represented by partial hepatectomy [19,20,61] . In contrast, only very few preneoplastic lesions of resistant BN rats grow autonomously after the end of the promoting stage; the majority of lesions remodel or no further evolve to neoplasia [61] .…”

Section: Cell Cycle Deregulationmentioning

confidence: 99%

See 1 more Smart Citation

Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis

Feo¹,

Frau²,

Pascale³

2008

WJG

Self Cite

View full text Add to dashboard Cite

Studies on rodents and humans demonstrate an inherited predisposition to hepatocellular carcinoma (HCC). Analysis of the molecular alterations involved in the acquisition of a phenotype resistant or susceptible to hepatocarcinogenesis showed a deregulation of G1 and S phases in HCC of genetically susceptible F344 rats and a G1-S block in lesions of resistant Brown norway (BN) rats. Unrestrained extracellular signal-regulated kinase (ERK) activity linked to proteasomal degradation of dual-specificity phosphatase 1 (DUSP1), a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex occurs in more aggressive HCC of F344 rats and humans. This mechanism is less active in HCC of BN rats and human HCC with better prognosis. Upregulation of iNos cross-talk with IKK/NF-kB and RAS/ERK pathways occurs in rodent liver lesions at higher levels in the most aggressive models represented by HCC of F344 rats and c-Myc-TGF-α transgenic mice. iNOS, IKK/NF-kB, and RAS/ERK upregulation is highest in human HCC with a poorer prognosis and positively correlates with tumor proliferation, genomic instability and microvascularization, and negatively with apoptosis. Thus, cell cycle regulation and the activity of signal transduction pathways seem to be modulated by HCC modifier genes, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.

show abstract

Role of HSP90, CDC37, and CRM1 as modulators of P16^INK4Aactivity in rat liver carcinogenesis and human liver cancer

Cited by 88 publications

References 39 publications

The androgen receptor and prostate cancer: A role for sexual selection and sexual conflict?

The androgen receptor and prostate cancer: A role for sexual selection and sexual conflict?

Targeting the oncogene and kinome chaperone CDC37

Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis

Contact Info

Product

Resources

About

Role of HSP90, CDC37, and CRM1 as modulators of P16INK4Aactivity in rat liver carcinogenesis and human liver cancer

Cited by 88 publications

References 39 publications

The androgen receptor and prostate cancer: A role for sexual selection and sexual conflict?

The androgen receptor and prostate cancer: A role for sexual selection and sexual conflict?

Targeting the oncogene and kinome chaperone CDC37

Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis

Contact Info

Product

Resources

About

Role of HSP90, CDC37, and CRM1 as modulators of P16^INK4Aactivity in rat liver carcinogenesis and human liver cancer