Lawrence A. Donehower, Ph.D.
Department of Molecular Virology & Microbiology
Tumor Suppressor Genes in Cancer
We are currently examining the role of tumor suppressor genes in cancer. 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. Subsequent experiments have centered on developing better mouse models for specific cancers, including osteosarcoma and rhabdomyosarcoma.
We are also studying p53 signaling pathways and have been studying a p53-induced phosphatase called PPM1D (WIP1) 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. Recently, we have been testing small molecule inhibitors of this phosphatase as a potential cancer therapeutic strategy.
One major new area of interest has been the development of computational approaches to identify and characterize genes and pathways associated with an assortment of human cancers. In collaboration with the Human Genome Sequencing Center at Baylor, we have been synthesizing data obtained from high throughput genomic and transcriptomic analytic platforms applied to large numbers of a variety of human cancers as part of The Cancer Genome Atlas research consortium. Our particular focus has been on the examination of p53 effects on cancer signaling patterns across a range of human cancers.
Baylor College of Medicine
One Baylor Plaza
Houston, TX 77030
Ph.D., The George Washington University
Postdoctoral, University of California, San Francisco
Awards, Appointments and Honors
1992 - Donehower et al. (1992) Nature paper named “Hot Paper” by The Scientist
2002 - Michael E. DeBakey Award for Excellence in Research, BCM
2002 - Tyner et al. (2002) Nature paper named “Exceptional Paper” by Faculty of 1000
2003 - Marc Dresden Award for Excellence in Graduate Education, BCM
The Cancer Genome Atlas Network (2012). Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330-337.
Darlington Y, Nguyen TA, Moon SH, Herron A, Rao, P, Zhu C, Lu X, Donehower LA. (2012). Absence of Wip1 partially rescues Atm deficiency phenotypes in mice. Oncogene 31:1155-1165.
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, Lozano G. (2009). 20 years studying p53 functions in genetically engineered mice. Nat. Rev. Cancer 9:831-841.
The Cancer Genome Atlas Network (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061-1068.
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.