Cyclin D1 and molecular chaperones: implications for tumorigenesis.
ABSTRACT We recently investigated the mechanisms of cyclin D1 action in human cancer using global analyses of gene expression. With an experimentally-determined expression signature for cyclin D1 overexpression, gene expression data from human tumors, and a novel data-mining method, we were able to reveal a previously unappreciated and apparently predominant functional interdependency between cyclin D1 and C/EBPbeta. Many of the genes we found to be affected by cyclin D1 overexpression are recognized as molecular chaperones or their regulators. Might this provide insights to the role of the cyclin D1-C/EBPbeta axis in carcinogenesis?
Article: Perspectives on c-Myc, Cyclin D1, and their interaction in cancer formation, progression, and response to chemotherapy.[show abstract] [hide abstract]
ABSTRACT: C-myc is an oncogene that functions both in the stimulation of cell proliferation and in and apoptosis. C-myc elicits its oncogenic activity by causing immortalization, and to a lesser extent the transformation of cells, in addition to several other mechanisms. C-myc may also enhance or reduce the sensitivity of cancer cells to chemotherapy, but how this dual function is controlled is largely unclear. Cyclin D1 (D1) is another oncogene that drives cell cycle progression; it acts as a growth factor sensor to integrate extracellular signals with the cell cycle machinery, though it may also promote apoptosis. C-Myc collaborates with TGFalpha, epidermal growth factor receptor, Ras, PI3K/Akt, and NF-kappaB. in part via coordination in regulation of D1 expression, because D1 is a common downstream effector of these growth pathways. Coordination of c-Myc with D1 or its upstream activators not only accelerates tumor formation, but also may drive tumor progression to a more aggressive phenotype. Because c-Myc may effect immortalization while D1 or its upstream activators elicit transformation, targeting c-myc and D1 may be a good strategy for cancer prevention. Moreover, since D1 imposes chemoresistance on cancer cells, targeting D1 may also be a good strategy for cancer chemotherapy, whereas practicioners should be cautious to downregulate c-myc for chemotherapy, since c-Myc may elicit apoptosis.Critical reviews in oncogenesis 12/2007; 13(2):93-158.
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ABSTRACT: Rb family members were the only demonstrated substrates of CDK4 until it was shown recently that Smad3, which plays a key role in mediating TGF-beta antiproliferative responses, is phosphorylated by both CDK4 and CDK2 in vivo and in vitro. CDK phosphorylation of Smad3 inhibits its transcriptional activity and antiproliferative function. The Rb pathway is disrupted in almost all human cancers. Most cancers contain high levels of CDK activity due to frequent inactivation of the p16 tumor suppressor or overexpression of cyclin D1. Therefore, disruption of the Rb pathway not only inactivates Rb, but also likely diminishes Smad activity, which may contribute to tumorigenesis and resistance to the TGF-beta growth-inhibitory effects in cancers. Although genetic mutation of Smad3 has not been reported, CDK phosphorylation of Smad3 may provide an epigenetic mechanism for inhibition of the tumor suppressive function of Smad3 during the early stages of tumorigenesis.Cell cycle (Georgetown, Tex.) 02/2005; 4(1):63-6. · 5.36 Impact Factor