Kanteti Prasad

Associate Professor,

Ph.D., Pune University (India), 1982

Room: E820 MSB, Tel: 312-413-3423

Email: kanteti@uic.edu

Various members of the Tumor Necrosis Factor Receptor (TNFR) family appear to mediate two seemingly opposite cellular functions, namely cell growth/differentiation and programmed cell death or apoptosis. CD27, a member of this family, is mainly expressed on discrete populations of T and B cells where it appears to provide crucial co-stimulatory signals for T cell activation, B cell differentiation and immunoglobulin synthesis. A role for CD27 has been implicated in various types of autoimmune disorders and certain B cell cancers. During our studies related to CD27 signaling, we were surprised to observe that ligation of CD27 by CD70 (its natural ligand) resulted in apoptosis. Unlike other members of the TNFR family, which mediate cell death, such as Fas and TNFR1, the cytoplasmic tail of CD27 lacks the necessary death domain. How then is CD27 able to induce apoptosis? In order to address this question, using the CD27 cytoplasmic tail as the bait in a yeast two-hybrid system, we cloned a novel molecule named Siva-1 that can induce apoptosis. Accordingly, we propose that despite the lack of an encoded death domain, CD27 by interacting with Siva-1 can induce apoptosis. Recently, we also discovered an alternate splice form of Siva-1, referred to as Siva-2, which cannot induce apoptosis. We plan to map the apoptotic region of Siva-1 and its binding site to the CD27 cytoplasmic tail, using several deletion as well as specific site-directed mutants of Siva-1. These studies are likely to generate a dominant negative mutant form of Siva, which will be invaluable in verifying the role of Siva in CD27 induced apoptosis. Since Siva is highly expressed in thymus, a major site of apoptotic activity, we plan to define the targets of Siva in thymus and study the relationship to CD27 and other TNFR family members. The structural features as well as the function are both conserved between human and mouse Siva-1/Siva-2. We therefore plan to generate transgenic mice that express human Siva-1 or Siva-2 and these models will be invaluable to unravel the biology of Siva and address in vivo questions related to the study of some of the functional aspects of CD27 and related TNFR family members. One of the immediate goals is also to raise monoclonal antibodies against human Siva, identify related family members and determine the down stream targets.