4. Regulation of Cell Death by pRB.

In addition to its role in blocking cell cycle, the RB tumor suppressor acts to promote survival and loss of RB leads to cell death. Evidence from mouse models and human cancer suggests that the dual roles of pRB in blocking cell proliferation and promoting cell survival have evolved to prevent the accumulation of cells with genetic lesions that could lead to cancer.

In the Macleod lab, we are investigating the molecular mechanisms that cause cells lacking the RB tumor suppressor to be hyper-sensitive to cell death induced by different stresses, including DNA damage, hypoxia, nutrient deprivation and death receptor ligation.

 

References
K Macleod, N Sherry, G Hannon, D Beach, T Tokino, K Kinzler, B Vogelstein & T Jacks: p53-Dependent and independent expression of p21 during cell growth, differentiation and DNA damage. Genes & Development 9:935-944 (1995).

K Macleod, Y Hu & T Jacks: Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. The EMBO Journal 15:6178-6188 (1996).

Tsai, KY, Hu, Y, Macleod, KF, Crowley, D, Yamasaki, L and T Jacks: Mutation of E2f-1 suppresses apoptosis and inappropriate S-phase entry and extends survival of Rb-deficient mouse embryos. Molecular Cell 2:283-292 (1998).

Marta Lipinski, Kay F. Macleod, Bart O. Williams, Denise Crowley, Tara L. Mullaney and Tyler Jacks: Cell-autonomous and non-cell autonomous functions of the Rb tumor suppressor in developing central nervous system. The EMBO Journal 20: 3402-3413 (2001).

Liu, H., Dibling, B., Spike B, Dirlam, A & Macleod, K: Novel functions of the RB tumor suppressor. Curr. Op. Gen. & Dev. 14, 55-64 (2004).