SUNY Stony Brook Pathology Department Faculty

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Function and regulation of the p53 gene family in normal cells and cancer cells

p53 is a multi-functional protein that controls a powerful stress response by integrating signals from many types of DNA damage, deregulated oncogenes and hypoxia, leading to p53 activation. Activated p53 elicits apoptosis, cell cycle arrest or senescence and is involved in maintaining genomic integrity, thus preventing tumor formation. Hence, loss of p53 function is a preeminent finding in human cancers, whether directly through mutation of p53 itself or through aberrant p53 regulation.

p53 induces apoptosis by a dual mode of action. p53 is a well characterized transcription factor inducing death-promoting target genes. In addition, we identified the transcriptionally-independent mitochondrial arm of p53-mediated apoptosis. Wild-type p53 protein but not tumor-derived mutants directly interact with and modulate the anti- and pro-death members of the Bcl-2 family of proteins that control the outer membrane permeability of mitochondria, thereby releasing apoptotic activators from the intermembranous space. Understanding the in vivo regulation and significance of this p53 activity is currently a focus of the lab. We are also investigating the role of ubiquitination in (dys)regulating subcellular p53 localization.

Two related but structurally complex family members called p63 and p73 have striking developmental functions. Another focus of our research is to elucidate their role in cancer which is complicated by their complex expression patterns and a lack of clear genetic data. We use a combination of human tumor material and mouse models to better understand their action in malignant transformation.
We found that ablation of the p73 gene reveals a p53-independet genome stabilization function that suppresses polyploidy and aneuploidy in primary cells. On the other hand, we found that human tumors often preferentially upregulate truncated forms of p73 (so-called DeltaTAp73 isoforms) that can act as dominant-negative inhibitors of wild-type p53 and TAp73 and might have prognostic significance in certain tumors.

Selected Publications (links will open a new browser window)

1) Talos F, Nemajerova A, Flores E, Petrenko O, Moll UM. p73 suppresses polyploidy and aneuploidy in the absence of functional p53. Mol Cell, in press (Aug 2007).

2) Marchenko ND, Wolff S, Erster S, Becker K, Moll UM. Monoubiquitylation promotes mitochondrial p53 translocation. EMBO J. 2007 Feb 21;26(4):923-34.

3) Becker K, Marchenko ND, Maurice M, Moll UM. Hyperubiquitylation of wild-type p53 contributes to cytoplasmic sequestration in neuroblastoma. Cell Death Differ. 2007 Jul;14(7):1350-60.

4) Nemajerova A, Mena P, Fingerle-Rowson G, Moll UM, Petrenko O. Impaired DNA damage checkpoint response in MIF-deficient mice. EMBO J. 2007 Feb 21;26(4):987-97.

5) Erster S, Palacios G, Rosenquist T, Chang C, Moll UM. Deregulated expression of DeltaNp73alpha causes early embryonic lethality. Cell Death Differ. 2006 Jan;13(1):170-3.

6) Palacios G, Moll UM. Mitochondrially targeted wild-type p53 suppresses growth of mutant p53 lymphomas in vivo. Oncogene. 2006 Oct 5;25(45):6133-9.

7) Talos F, Petrenko O, Mena P, Moll UM. Mitochondrially targeted p53 has tumor suppressor activities in vivo. Cancer Res. 2005 Nov 1;65(21):9971-81.

8) Petrenko O, Moll UM. Macrophage migration inhibitory factor MIF interferes with the Rb-E2F pathway. Mol Cell. 2005 Jan 21;17(2):225-36.

9) Concin, N., Becker, K., Slade, N., Erster, S., Mueller-Holzner, E., Ulmer, H., Daxenbichler, G., Zeimet, A., Zeillinger, R., Marth, C. and Moll, U.M. (2004) Transdominant DeltaTAp73 isoforms are frequently up-regulated in ovarian cancer. Evidence for their role as epigenetic p53 inhibitors in vivo. Cancer Res, 64, 2449-2460.

10) Mihara M, Erster S, Zaika A, Petrenko O., Chittenden T.,Pancoska P., Moll UM. p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003 Mar;11(3):577-90.

11) Petrenko, O., Zaika, A., Moll, U.M. (2003) deltaNp73 facilitates cell immortalization and cooperates with oncogenic Ras in cellular transformation in vivo. Mol Cell Biol, 23, 5540-5555.

12) Zaika, A.I., Slade, N., Erster, S.H., Sansome, C., Joseph, T.W., Pearl, M., Chalas, E. and Moll, U.M. (2002) DeltaNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors. J Exp Med, 196, 765-780.