Lawrence A. Donehower, Ph.D.
Departments of Molecular Virology and Microbiology and Molecular and Cellular Biology
Ph.D.: The George Washington University, Washington, D.C.
Postdoctoral training: University of California, San Francisco
Tumor Suppressors and Mouse Cancer and Aging Models
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, p53 prevents propagation of a cell with potentially oncogenic lesions.
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. 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.
Baylor College of Medicine
One Baylor Plaza, Jewish 819D
Houston, TX 77030
- Moon SH, Lin L, Zhang X, Nguyen TA, Darlington Y, Waldman AS, Lu X, Donehower LA. (2010). Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-H2AX and suppresses DNA double strand break repair. J Biol. Chem. 285:12935-12947.
- Donehower LA and Lozano G. (2009). Twenty years studying p53 functions in genetically engineered mice. Nature Rev. Cancer 9:831-841.
- Hinkal G, Parikh N, and Donehower LA. (2009). Timed somatic deletion of p53 in mice reveals age-associated differences in tumor progression. PLoS ONE 4:e6654.
- Ma O, Cai W-W, Zender L, Dayaram T, Herron AJ, Lowe SW, Man T-K, Lau CC and Donehower LA. (2009). Birc2 (cIAP1) and Birc3 (cIAP2), Amplified on chromosome 9, collaborate with p53 deficiency in mouse osteosarcoma progression. Cancer Res. 69:2559-2567.
- Lu X, Nguyen T-A, Moon S-H, Darlington Y, Sommer M and Donehower LA. (2008). The type 2C phosphatase Wip1: An oncogenic regulator of tumor suppressor and DNA damage response pathways. Cancer Metastasis Rev. 27:123-135.
- Gatza CE, Dumble M, Kittrell F, Edwards DG, Dearth RK, Lee AV, Xu J, Medina D and Donehower LA. (2008). Altered mammary gland development in the p53+/m mouse, a model of accelerated aging. Dev. Biol. 313:130-141.
- Lu X, Nguyen T-A, Jones SN, Oren M and 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 and Donehower LA. (2007). The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging. Blood 109: 1736-1742.
- Lu X, Nannenga B and 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 and Donehower LA. (2004). The p53-induced oncogenic phosphatase PPM1D Interacts with uracil DNA glycosylase and suppresses base excision repair. Mol. Cell 15, 621-634.