The Oncoprotein Kinase Chaperone <i>CDC37</i> Functions as an Oncogene in Mice and Collaborates with Both c-<i>myc</i> and Cyclin D1 in Transformation of Multiple Tissues

Stepanova, Lilia; Finegold, Milton J.; DeMayo, Francesco J.; Schmidt, Emmett V.; Harper, J. Wade

doi:10.1128/mcb.20.12.4462-4473.2000

Cited by 89 publications

(80 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Since cyclin D1-dependent activa- tion of CDK4 plays a key role in the inactivation of RB to permit G1-S transit through the cell cycle (Pavletich, 1999), increased cyclin D1 levels suggest an important mechanism for regulating mammary gland involution. Previous studies have shown that MMTVregulated expression of cyclin D1 in transgenic mice leads to mammary oncogenesis (Wang et al, 1994), and that cyclin D1 acts in a cooperative manner with the molecular chaperone CDC37 to accelerate mammary tumor formation (Stepanova et al, 2000). MMTV-Cdc25B mice also exhibited elevated cyclin D1 levels, delayed involution and hyperplasia , which was similar to the phenotype observed in MMTV-AKT1 mice.…”

Section: Discussionsupporting

confidence: 56%

Delayed mammary gland involution in MMTV-AKT1 transgenic mice

et al. 2002

View full text Add to dashboard Cite

AKT1/protein kinase Ba is a protein-serine/threonine kinase that regulates multiple targets involved in cell survival and cell cycle progression in a variety of cell types including breast cancer cells. To explore the role of Akt1 in mammary gland function and tumorigenesis, transgenic mice were generated that express human AKT1 under the control of the MMTV promoter. Virgin transgenic mice did not exhibit a dominant phenotype, but upon cessation of lactation, a notable delay in involution occurred compared to age-matched nontransgenic mice. The delay in involution coincided with increased hyperplasia as evidenced by an increased number of binucleated epithelial cells and a marked elevation in cyclin D1 expression in mammary epithelium. The delayed involution phenotype corresponded to increased phosphorylation of Thr308 in AKT1 and Ser136 in BAD, but not phosphorylation of Ser21 in GSK-3a. There was no evidence of mammary dysplasia or neoplasia during the lifespan of multiparous transgenic mice. These data suggest that AKT1 is involved in cell survival in the lactating and involuting mammary gland, but that overexpression of AKT1 alone is insu cient to induce transformation.

show abstract

Section: Discussionsupporting

confidence: 56%

Delayed mammary gland involution in MMTV-AKT1 transgenic mice

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Cdc37 was markedly absent on Akt from cells expressing NPM-ALK, whereas Cdk4 had similar amounts of Cdc37 from both cell lines. Interestingly, Cdc37 migrates as two bands on the SDS-PAGE [24], and both are represented at an apparent 1:1 ratio in the Akt immunoprecipitates. By contrast, only the more slowly migrating form of Cdc37 co-immunoprecipitates with Cdk4.…”

Section: Resultsmentioning

confidence: 99%

Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context

Theodoraki

Kunjappu

Sternberg

et al. 2007

Experimental Cell Research

View full text Add to dashboard Cite

Hsp90 inhibitors are currently in clinical trials for cancer therapy based on their ability to promote proteasomal degradation of oncogenic protein kinases and nuclear receptors. Results from recent studies suggest that cancer cells are more sensitive to these inhibitors than cells from healthy tissues. We analyzed an immortalized cell line Ba/F3, for sensitivity to the Hsp90 inhibitor geldanamycin in the absence and presence of the oncogenic tyrosine fusion kinase NPM-ALK expressed from a retroviral vector. Our results showed that NPM-ALK expression makes Akt and Cdk4 more resistant to degradation in the presence of geldanamycin, and there was a slightly reduced amount of apoptosis. The mechanism underlying the effect of NPM-ALK on Akt stability was probed by comparison of the turnover of the kinase after translation inhibition and geldanamycin treatment. We observed that Akt was degraded more rapidly in the presence of GA than upon translation inhibition without NPM-ALK expression. This suggests that NPM-ALK protects the mature kinase. Furthermore, Akt failed to bind to the Cdc37 chaperone in cells expressing NPMALK, which also correlates with increased Akt stability.

show abstract

“…Indeed, under forced Cdc37 expression cells become transformed, proliferate and tumors arise. When Cdc37 is overexpressed along with the proto-oncogene c-Myc, the effects of both agents become amplified and more and larger tumors arise in transgenic mice 15,8,14 . Indeed, Cdc37 levels are elevated in many clinical cancers 8 .…”

Section: Targeting Cdc37 In Cancermentioning

confidence: 99%

“…However, the Cdc37 promoter is devoid of canonical HSF1 binding elements and does not respond to HSF1 activation. A further clue that warrants exploration is that Cdc37 is overexpressed in prostate cancer and such cancers are induced by the forced expression of Cdc37 8,14 . As AR is one of the rare non-kinase clients for Cdc37, and is essential for proliferation and differentiation of prostatic epithelium, a role for AR would fit the profile 8 .…”

Section: Targeting Cdc37 In Cancermentioning

confidence: 99%

“…1-6 NIH Public Access 5 . However, the degree to which Cdc37 responds to the quality or quantity of clients in these contrasting proliferative states is yet to be determined.The amplified levels of Cdc37 in prostate cancer suggest that it may be of particular significance in this type of neoplasm 8,14,15 Indeed, in recent immunohistological studies, Cdc37 overexpression was found in 100% of neoplastic prostate tissue, compared with normal prostate 8 . Although the rationale for this is not certain, one rather compelling suggestion involves the role of Cdc37 in androgen signaling, a key pathway in prostatic cell growth.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

The Oncoprotein Kinase Chaperone CDC37 Functions as an Oncogene in Mice and Collaborates with Both c-myc and Cyclin D1 in Transformation of Multiple Tissues

Cited by 89 publications

References 71 publications

Delayed mammary gland involution in MMTV-AKT1 transgenic mice

Delayed mammary gland involution in MMTV-AKT1 transgenic mice

Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context

Targeting the oncogene and kinome chaperone CDC37

Contact Info

Product

Resources

About