Research Interests

Current research in our lab focuses on two major areas concerning p53 and apoptosis. One centers on addressing how p53 makes the choice of growth arrest vs. apoptosis. The other question aims at the cross-talk between apoptotic pathways mediated by death receptors and mitochondria.

The p53 choice.

One of the most intriguing questions in the p53 field is how a cell makes the decision to either enter growth arrest or undergo apoptosis upon p53 induction. There are two prevailing models regarding the choice of p53 response. In the preferential gene induction model, it is proposed that p53 preferentially induces pro-apoptotic genes upon death stimulation, while the pro-apoptotic genes are not activated during p53-mediated grow arrest. In another model, it is hypothesized that p53 always induce same set of genes after activation, including genes involved in both growth arrest and apoptosis. Activation of p53-mediated apoptosis requires additional and independent signaling. Our studies on Bax translocation during p53-mediated apoptosis support the later model. ax is up-regulated to similar levels by p53 during either growth arrest or apoptosis. However, Bax is in cng growth arrest and localizes to mitochondria during apoptosis. We further show that translocation of Bax from cytosol to mitochondria is required for p53-mediated apoptosis.          We have proposed a sequential model for p53-mediated growth arrest vs. apoptosis. In this model, we propose that one of the mechanisms underlining the decision making between growth arrest and apoptosis upon p53 induction is determined by “modulator proteins”. Induction of p53 results in an up-regulation of both cell growth regulating genes and pro-apoptotic factors. However, the pro-apoptotic factors, such as cytosolic Bax, remain inactive and cells enter growth arrest due to the expression of growth regulating genes such as p21 and GADD45 (Fig.1). In the presence of modulators which serve as co-activators of pro-apoptotic proteins to stimulate their apoptotic functions by inducing pro-apoptotic protein Bax translocation, cells undergo apoptosis (Fig. 1). The presence or absence of these modulators could account for the distinct responses to p53 induction in a wide variety of cells and under diverse conditions.

Figure 1. A sequential model for p53-mediated apoptosis vs. growth arrest. Various stress signals lead to p53 induction and transcription activation of p53 targets. As a result, effectors for both growth arrest (open circles ) and apoptosis (open triangles) are induced. However, the effectors of apoptosis remain inactive and cells enter growth arrest. The presence of modulators activates pro-apoptotic factors (filled triangles) then cell death prevails.

Mitochondria and death receptor cross-talk in apoptosis.

The signaling events to apoptosis can be divided into two distinct pathways, either intrinsically or extrinsically. In the extrinsic pathway, the apoptotic events are initiated by engaging “death receptors” belonging to the TNF family receptors such as TNFR1 and Fas. Activation of death receptors leads to the recruitment of an adapter protein FADD, which results in caspase 8 activation and subsequent activation of caspase 3 and apoptosis. In the intrinsic pathway, apoptosis is the result of activation of mitochondria and subsequent release of factors such as cytochrome c and Smac involved in various aspects of apoptosis. Although the apoptotic pathways through death receptors and mitochondria are capable of operating independently, accumulating evidence suggests that a cross-talk between the two pathways exists. Recent studies from our lab have shown that mitochondria are required for TRAIL-and FasL-induced apoptosis in human cancer cells. We show that the Bax null cancer cells are resistant to TRAIL/FasL-induced apoptosis. Bax deficiency has no effect on TRAIL/FasL-induced caspase 8 activation and subsequent cleavage of Bid; however, it results in an incomplete caspase 3 processing due to inhibition by XIAP. Release of Smac from mitochondria through TRAIL/FasL-caspase 8-tBid-Bax cascade is required to remove the inhibitory effect of XIAP and allow apoptosis to proceed. Inhibition of caspase 9 activity has no effect on TRAIL/FasL-induced caspase 3 activation and cell death, while expression of an active form of Smac in cytosol is sufficient to reconstitute TRAIL/FasL sensitivity in Bax deficient cells. Our results demonstrate for the first time that Bax-dependent release of Smac, not cyto c from mitochondria, mediates the contribution of mitochondrial pathway to TRAIL/FasL through death receptor-mediated apoptosis (Fig 2).

Selected Recent Publications

Relaix, F., X. Wei, W. Li, J. Pan, Y. Lin, D.D. Bowtell, D.A. Sassoon, and X. Wu, Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis. Proc Natl Acad Sci U S A, 2000. 97:. 2105-2110.

Deng, Y. and X. Wu, Peg3/Pw1 Promotes p53-Mediated Apoptosis by Inducing Bax Translocation from Cytosol to Mitochondria. Proc Natl Acad Sci U S A, 2000. 97: 12050-12055.

Buschmann, T., Lin, Y., Aithmitti, N., Fuchs, S. Y., Lu, H., Resnick-Silverman, L., Manfredi, J. J., Ronai, Z., and Wu, X.  Stabilization and activation of p53 by the coactivator protein TAFFII31. J. Biol. Chem., 2001. 276: 13852-13857.

Deng Y., Lin, Y., and Wu, X. Trail Induced Apoptosis Requires Bax-Dependent Mitochondrial Release of Smac/DIABLO.  Genes & Develop. 2002. 16:33-45

Contacts

Tel: 713-798-1516 (Office), 713-798-1619 (Lab)
Fax: 713-798-4161
Email: xiangwei@bcm.tmc.edu
Location: 
Alkek Building, Room N810
One Baylor Plaza
Baylor College of Medicine
Houston, TX 77030