MDM2 Overexpression Cooperates with Mutant CDK4 in Mammary Cell Transformation and Tumorigenesis
Abstract
In an effort to gain a better understanding of the consequence of deregulated CDK4 activity in vivo, the authors generated knock-in transgenic mice that express a tumor-derived mutant form of CDK4 (r24c). Interestingly, these mice are very prone to developing tumors of different cellular origins, including breast tumors. Since the p53 tumor suppressor pathway is an inhibitor of oncogene-induced transformation and is inactivated in a high percentage of mouse and human tumors, they decided to determine if inactivation of the p53 pathway is an important step in CDK4 mutant-induced tumorigenesis. The investigation revealed that MDM2 is overexpressed in 3 out of 10 breast tumors from these transgenic mice, and the authors have found no evidence that the p53 pathway is inactivated in the tumors that arise in these animals. MDM2 has oncogenic properties when overexpressed, and high amounts of the protein are present in human cancers. It is generally accepted that MDM2 promotes tumorigenesis by directly blocking the function of the p53 tumor suppressor. However, recent studies indicate that MDM2 promotes cell proliferation by mechanisms that are independent of inactivating p53, including by inhibiting the anti-proliferative activity of Transforming Growth Factor-Beta 1 (TGF Beta 1) in breast tumors. Considering that they have found no evidence for the loss of p53 function by p53 gene mutation or the loss of p19 (sup ARF) expression, the scope of this proposal is to address if MDM2 overexpression cooperates with mutant CDK4 in mammary cell transformation and tumorigenesis by affecting p53-independent proliferation control pathways.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2005
- Accession Number
- ADA456184
Entities
People
- Christopher Carbone
Organizations
- Temple University