Michael Karin Professor of Pharmacology Phone: 858-534-1361 Fax: 858-534-8158 E-mail: karinoffice@ucsd.edu

Key Words: Gene Expression, Signal Transduction, Transcription Factors, Oncogenes, Protein Kinases

Dr. Karin was born in Tel Aviv, Israel and received the Bachelor of Science degree in 1975 from Tel Aviv University, with a major in Biology. In 1975 he arrived in the US and in 1979 received a Ph.D. degree in Molecular Biology from the University of California, Los Angeles. Dr. Karin followed his graduate studies with postdoctoral fellowships at the Fox Chase Institute for Cancer Research, working in the laboratory of Dr. Beatrice Mintz, and the laboratory of Dr. John Baxter at the University of California, San Francisco. Dr. Karin joined the faculty at the University of California, San Diego in 1986, where currently he is a Distinguished Professor of Pharmacology.

Dr. Karin has received numerous awards including the Oppenheimer Award for Excellence in Research from the Endocrine Society, The Herman Beerman Lectureship from the Society of Investigative Dermatology, C.E.R.I.E.S. Research Award for Physiology or Biology of the Skin, The Grossman Lectureship form the American Gastroenterology Association and an American Cancer Society Research Professorship in 1999. Dr. Karin was elected to the National Academy of Sciences in 2005. Dr. Karin also serves on several advisory boards and was cofounder of Signal Pharmaceuticals (currently Celgene).

Dr. Karin's research interests focus on six areas of study. 1) Regulation of transcription in mammalian cells by cytokines, steroid hormones, growth factors, infections and adverse environmental conditions. Biochemical and genetic approaches have been utilized to isolate transacting regulatory proteins, which mediate responses to developmental, hormonal and environmental signals, by binding specific DNA sequences. Current efforts focus on understanding the regulation of gene transcription during infection, inflammation and injury. 2) Response of the human genome to stress. The molecular basis for the UV response, the mammalian counterpart of the bacterial SOS response is being studied by various molecular genetics techniques. 3) Protein kinase cascades and their role in growth control, cell differentiation and programmed cell death. These studies focus on the JNK and p38 MAP kinase cascades, their regulation and their roles in cellular regulation and specific gene induction. 4) The IKK/NF- B signaling pathway and its physiological and pathophysiological functions. We are most interested in studying IKK and NF- B as important links between chronic inflammation and cancer and also as mediators of chronic inflammatory and autoimmune diseases. These studies utilize biochemical as well as whole animal approaches. 5) Signaling by receptors involved in inflammation and innate immunity. We are studying the signaling mechanisms used by members of the TNF receptor family, Toll-like receptors (TLRs) and intracellular receptors for pathogen recognition, such as NOD2. We are interested in the mechanisms used by these receptors to activate protein kinases such as IKK and JNK and the role of ubiquitin ligases in these signaling events. We are also studying how these receptors control cell survival and death. 6) The regulation of mRNA turnover and translation. In addition to gene transcription, important control points in gene expression are mRNA turnover and translation. We are studying both the general mechanisms responsible for rapid mRNA degradation in mammals and the control of protooncogene and cytokine mRNA turnover and translation by extracellular signals. Dr. Karin made seminal contributions to the discipline of signal transduction describing how extracellular stimuli, including growth factors, cytokines, tumor promoters and UV radiation, regulate gene expression in eukaryotic cells. Starting with cloning of the human metallothionein IIA gene and analysis of its promoter, Karin and coworkers were the first to identify cis elements that mediate induction of cellular genes by stress signals, glucocorticoids and tumor promoters. This resulted in identification of several transcription factors, including AP-1, that recognize these cis elements. AP-1 was subsequently shown by Karin and coworkers to be composed of Jun and Fos proteins. This provided one of the first demonstrations that nuclear protooncoproteins function as transcription factors. Analysis of the mechanisms by which growth factors and UV radiation induce AP-1 activity led to identification of a major signaling pathway (the JNK MAP kinase cascade), elucidation of the mechanisms by which protein phosphorylation controls transcription factor activity and an explanation for the ability of membrane associated oncoproteins, such as Ras, to modulate gene transcription. Karin and coworkers have also described how proinflammatory stimuli regulate the activity of transcription factor NF- B and identified the IkB kinase (IKK) complex, which they have shown to be a major regulator of innate immunity and inflammation. Recently, Karin and coworkers have established the role of the IKK-NF- B pathway in providing a link between inflammation, infection and cancer. Genetic analysis of IKK function resulted in identification of a novel signaling pathway that controls development of the mammalian epidermis. Karin and coworkers were also the first to biochemically identify a cell type specific transcription factor (GHF-1/Pit1), demonstrate its kinship to homeodomain proteins and provide important insights to the mechanism of tissue specific gene expression.

Recent Publications

DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M. 1997. A cytokine-responsive I B kinase that activates the transcription factor NF- B. Nature 388:548-54.

Hu, Y., Baud, V., Oga, T. Kim, K., Kazuhiko, Y. and Karin, M. 2001. IKK controls formation of the epidermis independently of NF- B via a differentiation inducing factor. Nature 410:710-714.

Senftleben, U., Cao, Y., Xiao, G., Greten, F., Krahn, G., Bonizzi, G., Chen, Y., Hu, Y., Fong, A., Sun, S., Karin, M. 2001. Activation by IKK of a Second, Evolutionary Conserved, NF- B Signaling Pathway. Science. 293:1495-1499.

Chen, C-Y., Gherzi, R., Ong, S-E., Chan, E.L., Raijmakers, R., Pruijn, G.J.M., Stoecklin, G., Moroni, C., Mann, M., Karin, M., 2001. AU-binding proteins recruit the exosome to degrade ARE-containing mRNAs. Cell 107:451-464.

Greten, F.R., Eckmann, L., Greten, T.F., Park, J.M., Li, Z-W, Egan, L.J., Kagnoff, M.F. and Karin, M., 2004. IKK links inflammation and tumorigenesis in a mouse model of colitis associated cancer. Cell 118:285-296.

Sil, A. K., Maeda, S., Sano, Y., Roop, D. R. & Karin, M. (2004) IkB kinase-a acts in the epidermis to control skeletal and craniofacial morphogenesis. Nature 428, 660-4.

Gao, M., Labuda, T., Xia, Y., Gallagher, E. Fang, D., Liu, Y-C. and Karin, M. (2004) Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science 306, 271-5.

Hsu, L-C, Park, J.M., Zhang, K., Luo, J-L, Maeda, S., Kaufman, R. J., Eckmann, L., Guiney, D. G. and Karin, M., 2004. The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4. Nature 428:341-345.

Maeda, S., Hsu, LC, Liu, H., Bankston, L.A., Iimura, M., Kagnoff, MF., Eckmann, L., Karin, M., 2005. Nod2 mutation in Crohn's disease potentiates NF- B activity and IL-1 processing. Science 307:734-738.

Kamata, H., Honda, S, Maeda, S., Chang, L., Hirata, H., Karin, M., 2005. Reactive Oxygen Species Promote TNF -Induced Death and Sustained JNK Activation by Inhibiting Map Kinase Phosphatases. Cell 120:649-661.

Maeda, S., Kamata, H., Luo, J-L, Leffert, H., Karin, M., 2005. IKK Couples Hepatocyte Cell Death to Cytokine-driven Compensatory Proliferation that Promotes Chemical Hepatocarcinogenesis. Cell. 121:977-990.

Häcker, H. Redecke, V., Blagoev, B.,Kratchmarova, I., Hsu, L-C., Wang, G, Kamps, M., Raz, E., Wagner, H., Häcker, G., Mann, M., Karin, M. (2006) Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439, 204-7.

Chang, L., Kamata, H., Solinas, G., Luo, J.L., Maeda, S., Venuprasad, K., Liu, Y.C., Karin, M. (2006) The E3 ubiquitin ligase itch couples JNK activation to TNFa-induced cell death by inducing c-FLIP(L) turnover. Cell 124, 601-13.