Zhaohui Feng Assistant Professor UMDNJ Department of Radiation Oncology & Pharmacology The Cancer Institute of NJ UMDNJ - Robert Wood Johnson Medical School 195 Little Albany Street, Room 4556 New Brunswick, NJ 08901 (732) 235-8814 FAX - 7493 fengzh@umdnj.edu

p53, tumor suppression, energy metabolism and aging

As "the guardian of the genome”, tumor suppressor p53 plays a critical role in tumor prevention. p53 is the most frequently-mutated gene in human tumors; over 50% of all tumors harbor mutations in the p53 gene. As a transcription factor, once p53 is activated it transcribes its target genes to initiate various cellular responses, including cell cycle arrest, apoptosis or senescence to prevent tumor formation. Recent studies are beginning to define novel functions of p53, including the regulation of energy metabolism, IGF-1/mTOR pathways, and aging. These findings suggest important functions of p53 in various cellular processes in addition to tumor suppression.

We are interested in the following research themes: 1) p53 and cellular energy metabolism. Metabolic changes (e.g. Warburg effect) are a hallmark of tumor cells, and have been recently identified as a key contributor to malignant progression. Recently, p53 has been shown to be directly involved in the regulation of mitochondrial respiration and inhibition of the Warburg effect. We are indentifying novel p53 target genes which are directly involved in the regulation of cellular energy metabolism and how they contribute to tumor suppression. 2) p53 and microRNAs. p53 protein levels and activity are under a tight and complex regulation in cells to maintain its normal functions. Recent studies show that MicroRNAs are a class of endogenously expressed, small noncoding regulatory RNA molecules, which play a key role in the regulation of gene expression. We are identifying microRNAs targeting p53 and critical regulators in the p53 pathway to study how microRNAs are involved in tumorigenesis or tumor suppression.  3) p53 and aging. Aging is subject to regulation by genes that reside in pathways that have been conserved during evolution. The IGF-1/mTOR/p53 pathways are among those conserved pathways that impact upon longevity and aging-related diseases. Cancer is a disease of aging, and the accumulation of DNA mutations in critical genes (e.g. p53) in individual cells over a lifetime is thought to be the reason. Our recent finding demonstrates that p53 function declines with age especially in response to stress in mouse models, which may contribute to an enhanced mutation frequency and tumorigenesis in aged populations in addition to mutation accumulation. These findings suggest the important role of p53 in regulation of aging and aging-related diseases. We are interested in studying mechanisms accounting for the decline of the p53 function in aging process and its effects on mutation, tumorigenesis and aging.

Selected Publications

Hu W, Feng Z, Levine AJ. (2009) The regulation of human reproduction by p53 and its pathway. Cell Cycle. 8(22).

Kang H., Feng Z., Atwal G.S., Sun Y., Murphy M.E., Rebbeck T.R., Rosenwaks, Z., Levine, A.J. and Hu, W. (2009) Single nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc Natl Acad Sci USA. 106 (24): 9761-6.

Feng Z., Hu W., Rajagopal G., Levine A.J. (2008) The Tumor Suppressor p53; Cancer and aging. Cell Cycle. 7(7):842-847.

Feng Z. , Hu W., Teresky A.K., Hernando E., Cordon-Cardo C., Levine A.J. (2007) Declining p53 function in aging: a possible mechanism for high tumor incidence in older populations. Proc Natl Acad Sci USA .104(42):16633-16638.

Hu W., Feng Z (co-first author) , Teresky AK., Levine AJ. (2007) p53 regulates maternal reproduction through LIF. Nature 450 (7170): 721-724.

Feng Z. , Hu W., de Stanchina E., Teresky A.K., Jin S., Lowe S., Levine A.J. (2007) The regulation of AMPK b 1, TSC 2 and PTEN expression by p53: Stress, cell and tissue specificity and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res. 67(7):3043-3053.

Feng Z. , Jin S., Zupnick A., Hoh J., de Stanchina E., Lowe S.W, Prives C, Levine A.J. (2006) p53 Tumor Suppressor Protein regulates the levels of Huntingtin Gene expression. Oncogene 25:1-7.

Levine A.J., Feng Z., Mak T.W., You H., Jin S. (2006) Coordination and communication between the p53 and IGF1-AKT-Tor signal transduction pathways. Genes & Development 20:267-275.

Feng Z. , Hu W., Yu H., Tang M.S. (2006) Acrolein is a major cigarette-related lung cancer agent: preferential binding at p53 mutational hotspots and inhibition of DNA repair. Proc Natl Acad Sci U S A 103:15404-15409.

Feng Z., Zhang H., Levine A.J., Jin S. (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A 102:8204-8209.

Feng Z. , Hu W., Tang M.S. (2004) Trans-4-hydroxy-2-nonenal inhibits nucleotide excision repair in human cells: a possible mechanism for lipid peroxidation-induced carcinogenesis. Proc Natl Acad Sci U S A 101:8598-8602.

Feng Z. , Hu W., Chasin L.A., Tang M.S. (2003) Effects of genomic context and chromatin structure on transcription-coupled and global genomic repair in mammalian cells. Nucleic Acids Res 31:5897-5906.

Feng Z. , Hu W., Rom W., Costa M., Tang M.S. (2003) Chromium(VI) exposure enhances polycyclic aromatic hydrocarbon- DNA binding at the p53 gene in human lung cells. Carcinogenesis 24:771-778.

Feng Z., Hu W., Chen J.X., Pao A., Li H., Rom W., Hung M.C., Tang M.S.(2002) Preferential DNA damage and poor repair determine ras gene mutational hotspot in human cancer. J Natl Cancer Inst. 94:1527-1536.

Feng Z., Hu W., Komissarova E., Pao A., Hung M.C., Adair G.M., Tang M.S. (2002) Transcription-coupled DNA repair is genomic context-dependent. J Biol Chem. 277:12777-12783.