Programmed cell death, or apoptosis, is an active form of cellular suicide that functions physiologically to ensure that superfluous or unwanted cells are eliminated. The oncoprotein, Bcl-2, counters apoptosis in many instances, and when expressed in malignant cells often renders chemotherapy ineffective. Bcl-2 also provokes temporary refractoriness to mitogen stimulated cell proliferation but how this effect relates to its anti-apoptotic function was not previously clarified. In this proposal, the investigators now demonstrate that Bcl-2 in fact possesses two separate functions; ie. it increases a cell's inherent resistance against programmed cell death, and independently also delays cell proliferation. This suggests a metazoan strategy in which proliferation of cells with cell-autonomous resistance to apoptosis is inherently restricted, and argues that an overriding mitogenic signal and/or selective disabling of Bcl-2's antiproliferative effect is required for the proliferation of Bcl-2 expressor cells. The temporal correlation seen between Bcl-2's phosphorylation and its effect on cell proliferation suggests this post-translational modification may represent one such inactivation mechanism. Bcl-2 kinase initiated inactivation of Bcl-2's antiproliferative function may contribute to the secondary malignant transformations of Bcl-2 expressing indolent tumors, such as follicular lymphoma. Their proposed research program aims to examine the relation of Bcl-2's phosphorylation to its antiproliferative effect, to identify the kinase responsible for Bcl-2's phosphorylation and to examine its role in malignant transformation of Bcl-2 expressing indolent tumors. In addition, the wish to identify the mechanism by which Bcl-2 delays cell cycle progression.
| Huh, W K; Gomez-Navarro, J; Arafat, W O et al. (2001) Bax-induced apoptosis as a novel gene therapy approach for carcinoma of the cervix. Gynecol Oncol 83:370-7 |
| Poommipanit, P B; Chen, B; Oltvai, Z N (1999) Interleukin-3 induces the phosphorylation of a distinct fraction of bcl-2. J Biol Chem 274:1033-9 |
| St Clair, E G; Anderson, S J; Oltvai, Z N (1997) Bcl-2 counters apoptosis by Bax heterodimerization-dependent and -independent mechanisms in the T-cell lineage. J Biol Chem 272:29347-55 |
