Regulation of cell proliferation and survival by Rb, cyclin/Cdk, and cell type specific regulators
The retinoblastoma protein (Rb) is a prototype tumor suppressor. In addition to retinoblastomas, Rb mutations have been found in significant frequencies in cancers of other tissues such as the bone, lung, bladder, and prostate. Our laboratory is studying how Rb controls cell proliferation and survival in collaboration with general cell cycle regulators and cell type-specific regulators. At present, we are pursuing the following three lines of investigation.
(1) The best established biochemical function of Rb is repression of the transcription factor E2F, which is believed to account for Rb's ability to induce G1-to-S phase cell cycle block. However, the kinetics of repression of E2F regulated genes lags behind the onset of G1-to-S phase cell cycle block in timed Rb reexpression experiments and certain partial penetrance Rb mutants do not repress E2F but can still induce G1-to-S phase cell cycle arrest. We are studying how the ubiquitin ligase component Skp2 functions in a pathway with Rb to control cell proliferation.
(2) While Rb's function in cell cycle regulation improves our understanding of Rb as a central regulator of proliferation regulation, the reason for the apparent cell type specific patterns of Rb mutations in cancer remains unexplained. We hypothesized that certain functions of Rb may depend on certain cell type-specific regulators, which may also be mutated in carcinogenesis of that type of cells. Using this rationale, we discovered an apoptosis inducing activity of Rb that is dependent on the androgen receptor in prostate cancer cells. We are investigating the molecular mechanisms for this functional collaboration between Rb and the AR.
(3) While run-away cell proliferation is an hallmark of cancer, appropriate stimulation of cell proliferation often is the key to the success of cell-based therapies. We are applying knowledge learned from studying cell proliferation regulation to cell based therapy. Inactivation of the cyclin-dependent kinase inhibitor p27Kip1 in the mouse led to increases in cell numbers of many organs that remain otherwise normal. One such organ is the liver. We have demonstrated that inactivation of p27 in mouse hepatocytes increased their proliferation potential after their transplantation into failing livers to rescue the hosts. We are currently using more sophisticated techniques to determine whether such advantages will be applicable to humans.
1. Ji, P., Goldin, L., Ren, H., Sun, D., Guardavaccaro, D., Pagano, M., and Zhu, L. Skp2 contains a novel cyclin A binding domain that directly protects cyclin A from inhibition by p27. J. Biol. Chem. 281:24058-24069 (2006)
2. Sun, D., Melegari, M. Sridhar, S., Rogler, C.E., and Zhu, L. A multi-miRNA hairpin method that improves gene knockdown efficiency and provides linked multi-gene knockdown. BioTechniques I41:59-63. (2006)
3. Ji, P., Jiang, H., Rekhtman, K., Bloom, J., Ichetovkin, M., Pagano, M., and Zhu, L. An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial penetrance Rb mutant. Molecular Cell 16:47-58 (2004)
4. Wang, X., Deng, H., Basu, I. and Zhu, L. Induction of androgen receptor-dependent apoptosis in prostate cancer cells by the retinoblastoma protein. Cancer Research. 64:1377-1385 (2004)