Transcription factors AP-1 and NF-kB are activated by a variety of physiological and pathological stimuli. Xenobiotics and therapeutic agents also modulate the activities of these transcription factors and thereby affect expression of their target genes. AP-1 activation is linked to the control of cell proliferation and is effected by tumor promoters, while anti-tumor promoters inhibit AP-1 activity. Therefore, agents that modulate the AP-1 activity have profound effects of cell proliferation and neoplastic transformation. NF-kB activation, on the other hand, plays a key role in induction of immunity and inflammatory responses. Therefore, xenobiotics that activate NF-kB can cause inflammatory disorders, while those that interfere with NF-kB activation are immunosuppressive. Dr. Karin proposes to examine the molecular mechanisms by which xenobiotics affect AP-1 and NF-kB activities, by studying their effects on several protein kinases, JNK, p38 and IkB kinase that play key roles in AP-1 and NF-kB activation. These studies will provide molecular explanation to effects of various xenobiotics, including alkylating agents, oxidants and antioxidants on cellular gene expression. There are conflicting indications that AP-1 and the protein kinases that stimulate its activity, JNK and p38, could be involved in either protection against adverse environmental conditions or in induction of apoptosis and cytotoxicity. He will examine the physiological role of AP-1 and proteins that regulate AP-1 activity in conferring resistance or sensitivity to various drugs by the use of cell lines derived from """"""""knockout"""""""" mice deficient in these factors. More specifically, he will: 1) Determine whether JAB1 (a coactivator for c-Jun or JunD) and its targets are involved in conferring drug resistance in mammalian cells; 2) Determine the mechanism by which certain translation and glycosylation inhibitors lead to activation of JNK and p38; 3) Determine the mechanism by which alkylating agents lead to JNK and p38 activation; 4) Investigate the role of c-Jun and AP-1 in cellular sensitivity or resistance to alkylating agents; 5) Investigate the role of JNK and p38 in mediating cellular responses to alkylating agents and other xenobiotics and; 6) Identify the IkB kinase and investigate its regulation by oxidants and antioxidants.
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