PUMA couples the nuclear and cytoplasmic proapoptotic function of p53

Science 309, 1732-1735 (2005)

Speaker: 蔡志文                                                      Time: 13:10-14:00, Nov. 30, 2005

Commentator: 林以行  老師                                  Place: Room 601

Abstract:

During stress responses, the tumor suppressor p53 accumulates in the nucleus and regulates the expression of apoptosis-inducing genes.  In addition to its transcription regulatory role, p53 may directly activate the proapoptotic protein BAX to promote mitochondria outer membrane permeabilization (MOMP) and apoptosis.  The activation of BAX is suppressed by the interaction of p53 with Bcl-xL (1).  PUMA (p53-upregulated modifier of apoptosis), a proapoptotic BH3-only protein, is a transcriptional target of p53.  It has been shown that PUMA is an essential mediator in p53-dependent apoptotic pathways (2).  PUMA interacts with Bcl-xL and promotes the mitochondrial translocation of BAX and apoptosis (3).  In this paper, the authors studied the tripartite nexus between p53, Bcl-xL and PUMA in response to stress stimuli.  After UV treatment, Bcl-xL interacted with p53 and PUMA.  The increased expression of PUMA induced the release of p53 from Bcl-xL and consequent BAX activation.  Furthermore, PUMA failed to overcome the inhibition of p53-mediated apoptosis by a mutant Bcl-xL^G138A which did not bind to the BH3-only proteins.  Together, nuclear p53 induces the expression of PUMA.  Although PUMA itself can not trigger the mitochondria damage and cell death, PUMA displaces cytoplasmic p53 from Bcl-xL, allowing p53 to induce the BAX activation and MOMP in p53-dependent apoptosis.

References:

1.      Chipuk, J. E. et al. Direct activation of BAX by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303, 1010-1014 (2004).

2.      Jeffers, J. R. et al. PUMA is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 4, 321-328 (2003).

3.      Yu, J. et al. PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc. Natl. Acad. Sci. U.S.A 100, 1931-1936 (2003).