Deregulation of the apoptotic pathway plays a critical role in the development of cancer. The identification and characterization of apoptotic genes involved in the deregulation of apoptosis is critical for the development of novel therapeutic approaches. He has identified CIPER, a gene that regulates both apoptosis and NF-kB activation. CIPER (also called bc110) has been found to be located at the breakpoint regions of t(1;14) (p22;q32), a recurrent chromosomal location associated with mucosa-associated lymphoid tissue (MALT) B-cell lymphoma. Importantly, the CIPER/bc110 product is frequently mutated in lymphomas of various histological types. Sequence analysis revealed that CIPER encodes a protein containing a caspase-recruitment domain (CARD) in its amino terminus and a C-terminal region rich in serine and threonine residues. Muational analysis revealed that two regions of CIPER, the CARD and a region just outside the CARD, are critical for NF-kB-inducing activity. N-terminal region of CIPER containing the CARD was sufficient and necessary for NF-kB-inducing activity. Point mutations in highly conserved residues in the CARD of CIPER disrupted the ability of CIPER to activate NF-kB and form homodimers, indicating that the CARD is essential for NF-kB activation and dimerization. He has evidence that CIPER interacts with IKKy(also called Nemo), the regulatory subunit of the IkB kinase (IKK) complex. Their hypothesis is that CIPER/bc110 promotes tumor development via a NF-kB activation pathway that is deregulated in cancer. The focus of this grant application is the molecular and functional characterization of CIPER. He is proposing a series of Aims to further define the mechanism by which CIPER promotes apoptosis and NF-kB activation. The experiments outlined in this application should provide important insight into the physiological role of CIPER in cellular processes and the mechanism by which it promotes cancer development.
