Sabapathy, Kanaga

Research Interests:

The goal of our research is to understand the nature of molecular changes leading to carcinogenesis, so that efficient therapeutic strategies can be developed to eradicate cancerous cells. In order to achieve our goals, we are focusing on understanding the p53/p73 tumour suppressor and the c-Jun proto-oncogene pathways, which regulate cell-fate in response to a multitude of environmental/stress factors. All 3 gene-products are transcription factors involved in regulating gene expression, and hence, their functional status is critical in determining cellular fate.

Although p53 and p73 belong to the same family of tumour-suppressors, p53 is mutated in more than 50% of all human cancers whereas p73 is over-expressed in many of them. P73 is more complex as it is heavily spliced at the carboxy-terminus and the usage of an internal promoter in intron 3 results in the generation of a truncated protein (the delta N) that has oncogenic properties. We are focusing on understanding the regulation of both p53 and p73, particularly with reference to induction of cell death. In addition, the cause and consequence of overexpression of p73 in human cancers is being investigated. Both “knock-in” mouse models and mammalian genetic screens are being employed to address these questions.

The proto-oncogene c-Jun is an immediate-early gene that is activated by a plethora of signals. Expression of c-Jun has been shown to induce both cell death and proliferation. How c-Jun executes such opposite effects is still enigmatic. We are focusing on understanding how c-Jun cooperates with various co-activators in bringing about these effects. In addition, the differential regulation of c-Jun by the c-Jun-N-terminal kinases (JNKs) and others, as well as characterization of the roles of the different c-Jun N-terminal kinase (JNK) family members, are being undertaken.

Selected Publications:

Sabapathy, K, M. Klemm, R. Jaenisch and E.F. Wagner. “Regulation of ES cell differentiation by functional and conformational modulation of p53”. EMBO J. 16(20): 6217-6229, 1997.

Sabapathy, K, Y.L. Hu, T. Kallunki, M. Schreiber, J.P. David, W. Jochum, E.F.Wagner, and M.Karin. " JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development”. Curr Biol. 11:116-25, 1999.

Sabapathy, K, W. Jochum, K. Hochedlinger, L. Chang, M. Karin and E.F. Wagner. "Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2". Mech. of Develop. 89(1-2):115-124, 1999.

Sabapathy, K, T. Kallunki, J.P. David, M. Karin and E.F. Wagner. “c-Jun NH2-Terminal Kinase (JNK)1 and JNK2 play similar and stage-dependent roles in regulation of T cell apoptosis and proliferation”. J.Exp. Med. 193: 317-328. 2001.

Sabapathy, K, K. Hochedlinger, S.Y. Nam, A. Bauer, M. Karin and E.F. Wagner. “Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation”. Molecular Cell. 15(5):713-25. 2004.

Sabapathy, K. and E.F. Wagner. “JNK2 – A negative regulator of cellular proliferation”. Cell Cycle. 3(12):1520-3. 2004.

Lee, M.K., M.P. Hande and K. Sabapathy. “Ectopic mTERT expression in mouse embryonic stem cells does not affect differentiation but confers resistance to differentiation- and stress-induced p53-dependent apoptosis”. J. Cell Science. 118(4):819-29. 2005.

Toh, W.H., S. Kyo and K. Sabapathy. “Relief of p53-mediated telomerase suppression by p73”. J. Biol Chem. 280(17):17329-38. 2005.

Dulloo,I. and K. Sabapathy. “Transactivation-dependent and independent regulation of p73 stability.” J Biol Chem. 280:28203-14. 2005.

Siddique, M.M., C. Balram, L. Fiszer-Maliszewska, A.Aggarwal, A. Tan, P. Tan, K.C. Soo and K. Sabapathy. “Evidence for selective expression of the p53 codon 72 polymorphs: implications in cancer development“. Cancer, Epidem., Biomarkers & Prevention. 14:2245-52. 2005.

Vikhanskaya, F., M.M. Siddique, M. Broggini and K. Sabapathy. “Evaluation of the combined effect of p53 codon 72 polymorphism and hot-spot mutations in response to anticancer drugs”. Clinical Cancer Research. 11:4348-56. 2005.

Siddique, M.M. and K. Sabapathy. “Trp53-dependent DNA-repair is affected by the codon 72 polymorphism”. Oncogene. 25:3489-500. 2006.

Tong, W.M., M.K.Lee, D. Galendo, Z.Q. Wang and K. Sabapathy. “Aflatoxin-B1 exposure does not lead to p53 mutations but results in enhanced hepatocellular carcinoma formation in Hupki (human p53 knock in) mice”. Int. J. Cancer. 119:745-9. 2006.

Hettinger, K., F. Vikhanskaya, M.K.Poh, M.K.Lee, I. de Belle, J.T. Zhang, S.A.G. Reddy and K. Sabapathy. “c-Jun promotes cellular survival by suppression of PTEN“. Cell, Death & Diffen. 14:218-29. 2007.

Vikhansyaka, F., M.K. Lee, M. Mazzoletti, M. Broggini and K. Sabapathy. “Cancer-derived p53 mutants suppress p53-dependent target gene expression –potential mechanism for gain of function of mutant p53”. Nucliec Acid Research. 35:2093-104. 2007.

Vikhansyaka, F., W.H. Toh, I. Dulloo, Q. Wu, L. Boominathan, H.H. Ng, K. Vousden and K. Sabapathy. “p73 supports cellular growth through c-Jun-dependent AP-1 transactivation”. Nature Cell Biol. 9:698-705. 2007.

Phang, B.H. and K. Sabapathy. “The codon 72 polymorphism-specific effects of human p53 are absent in mouse cells – implications on generation of mouse models”. Oncogene. 26:2964-74. 2007.

Lee, M.K. and K. Sabapathy. “The R246S hot-spot p53 mutant exerts dominant-negative effects in embryonic stem cells in vitro and in vivo.” J. Cell Science. In press. 2008.

Sabapathy, K. and S.Y.Nam. “Defective MHC class I antigen surface expression promotes cellular survival through elevated ER stress and modulation of p53 function.” Cell, Death & Diffen. In press. 2008.

S.S. Lum, H.W. Chua, H. Li, W.F.Li, N. Rao, J. Wei, Z. Shao and K. Sabapathy. “MDM2 SNP309 G allele increases risk but the T allele is associated with earlier onset-age of sporadic breast cancers in the Chinese population.” Carcinogenesis In press. 2008.