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We are currently examining the role of tumor suppressor genes in cancer and aging.  Tumor suppressor genes encode negative regulators of cell growth and are often mutated in human cancers.  The p53 tumor suppressor gene is our current focus.  About half of all human cancers have mutations in the p53 gene, indicating that loss of its function is an important contributing factor in cancer development.   p53 acts as a transcription factor that regulates many target genes that participate in cell cycle checkpoints that respond to DNA damage or initiate programmed cell death (apoptosis). In either case, the cell will be prevented from propagating damaged DNA templates that may ultimately form oncogenic lesions and increase the likelihood of the cell becoming cancerous. Thus, p53 is critical for preservation of genomic integrity and cancer prevention.

To explore the impact of p53 loss on tumorigenesis in a mammalian model, we have generated mice with inactive p53 genes in their germ line. The mice with inactivated p53 develop normally but are highly susceptible to a variety of cancers at a very early age. We are currently characterizing the p53-deficient mouse model in an attempt to elucidate the molecular and biological mechanisms by which loss of p53 predisposes the cell to cancer. In addition, we have generated mice with an apparent hyperactive version of p53. These mice are more resistant to cancer than normal mice. One very interesting effect in the hyperactive p53 mutant mice is that they exhibit early aging-associated phenotypes along with shortened longevity. Thus, in addition to its role in preventing cancer, p53 may also be important in regulating the aging process in mammalian organisms. We are currently analyzing these p53 mutant mice to better understand the molecular mechanisms by which p53 might influence the aging process.

Finally, we are also studying p53 signaling pathways and have been studying a p53-induced phosphatase called PPM1D that downregulates p53 in a negative feedback regulatory loop.   In some human tumors this phosphatase is overexpressed and probably contributes to tumor formation by inactivating the tumor suppressor functions of p53.  We hope to learn more about p53 functions by studying p53 targets such as PPM1D.

Recent Publications (PubMed)

Gatza CE, Dumble M, Kittrell F, Edwards DG, Dearth RK, Lee AV, Xu J, Medina D, Donehower LA. (2008).  Altered mammary gland development in the p53+/m mouse, a model of accelerated aging.
Dev. Biol. 313:130-141.

Lu X, Ma O, Nguyen TA, Jones SN, Oren M, Donehower LA.  (2007). The Wip1 Phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop.  Cancer Cell 12:342-354.

Dumble M, Moore L, Chambers S, Geiger H, Van Zant G, Goodell M, Donehower LA. (2007). The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging. Blood 109:1736-1742.

Lu X, Nannenga B, Donehower LA. (2005). PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes & Dev. 19: 1162-1174.

Lu X, Bocangel D, Nannenga B, Yamaguchi H, Appella E, Donehower LA (2004) The p53-induced oncogenic phosphatase PPM1D interacts with uracil DNA glycosylase and suppresses base excision repair. Mol. Cell 15:621-634.

Tyner SD, et al. (2002) p53 mutant mice that display early aging associated phenotypes. Nature 415:45-53