NF-Kappa B regulation by Bcl10 in liver cancer

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DESCRIPTION (provided by applicant): Dr. Lakita G, Cavin, the Candidate, has been a postdoctoral research trainee at the University of Tennessee in the lab of Dr. Marcello Arsura since June 2001 where she has played a prominent role in a project pertaining to the role of nuclear factor-kappaB (NF-kappaB) during hepatic oncogenesis. The experience and the knowledge gained during her training has inspired her to seek an independent position in academia where she will lead a team of capable scientist and researchers to further pursue her interests in liver cancer research. Over the past, the incidence rate of hepatocellular carcinomas (HCCs) as well as its morbidity in the U. S. has been steadily increasing due to an increment of hepatitis B and C viral infections. Thus, a better understanding of the mechanism/s leading to hepatic tumor progression is needed to design more effective therapies for the treatment of HCCs. Dr. Gavin's studies have implicated constitutive nuclear factor-kappaB (NF-kappaB) activation in liver neoplastic progression through protection from cell death and induction of cell growth. While the function of NF-kappaB during hepatic oncogenesis is well established, the mechanism/s of NF-kappaB activation still remains to be identified. In preliminary studies, the Candidate has shown that epidermal growth factor receptor (EGFR) signaling and the BcMO gene play a role in NF-kappaB activation in experimentally derived murine HCCs. Thus, her proposal plans to determine the biochemical parameters and functional consequences of BcMO- and EGFR-mediated activation of NF-kappaB in liver tumor progression. In specific Aim 1, Dr. Cavin will determine the role of Bcl10-mediated ubiquitination of IKK-gamma during aberrant activation of NF-kappaB in TGF-alpha/c-myc bitransgenic HCCs. In Aim 2, she will determine the functional impact of the EGFR/P(l)3K/Akt axis in constitutive activation of NF-KappaB and cell survival of murine and human HCCs. Finally, in Aim 3, she will determine the interplay between the EGFR/PI(3)K/Akt axis and the BcMO/IKK-gamma pathway in NF-kappaB activation. The characterization of the pathway/s leading to NF-kappaB activation during liver neoplastic development will provide venues for the development of small molecule inhibitors of NF-kappaB as potential adjuvants for liver cancer treatment.