Vincent L. Cryns, MD Associate Professor Medicine Molecular Mechanisms of Cancer Cell Death (Apoptosis) Curricula: Cancer Biology Cell Biology E-mail:   v-cryns@northwestern.edu

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Our laboratory focuses on molecular mechanisms of cancer cell death (apoptosis). Caspases are a conserved family of proteases that play a critical role in the execution of apoptosis. One of our major interests is the regulation of caspase activation by heat shock proteins. We have recently demonstrated that the heat shock protein aB-crystallin negatively regulates apoptosis by a novel mechanism: it inhibits the activation of caspase-3 (and possibly other caspases). In addition, we have shown that aB-crystallin is commonly expressed at high levels in a variety of cancers and confers resistance to chemotherapy-induced apoptosis. Our long-term goals include detailed structure-function analyses of aB-crystallin's anti-apoptotic domains and selective inhibition of aB-crystallin by a variety of approaches in an effort to sensitize tumors to chemotherapy-induced apoptosis. In tandem with these studies, we are also examining the anti-apoptotic mechanisms of other heat shock proteins (especially, Hsp27 and HspB2).

A second major interest of our group is the identification and characterization of the downstream targets of caspases whose proteolytic cleavage promotes apoptotic cell death. To this end, we have recently developed a novel expression cloning strategy to rapidly and systematically isolate caspase substrates. We are particularly interested in determining the functional significance of substrate cleavage, i.e., how does caspase cleavage of a given substrate contribute to the execution of apoptosis. As an example of this work, we identified the DNA repair protein RAD21 as a novel caspase substrate using this approach and demonstrated that caspase proteolysis of this nuclear protein promotes apoptosis by generating a pro-apoptotic cleavage product.

The overall goal of these studies, then, is to gain a better understanding of the molecular mechanisms of cancer cell death. We believe these new insights will lead to improved, highly selective treatments for cancer.

Research Topics

• apoptotic signal transduction
• regulation of cancer cell death by heat shock proteins
• caspase proteolytic signaling

Publications:

Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwal S, Guillozet AL, Lu M, Fu Y, Garcia-Sierra F, LaPointe N, Miller R, Berry RW, Binder LI, Cryns VL. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci USA 2003; 100:10032-10037

Chen F, Chang R, Trivedi M, Capetanaki Y, Cryns VL. Caspase proteolysis of desmin produces a dominant negative inhibitor of intermediate filaments and promotes apoptosis. J Biol Chem 2003; 278:6848-6853.

Kamradt MC, Chen F, Sam S, Cryns VL. The small heat shock protein aB-crystallin negatively regulates apoptosis during myogenic differentiation by inhibiting caspase-3 activation. J Biol Chem 2002; 277:38731-38736.

Chen F, Kamradt M, Mulcahy M, Byun Y, Xu H, McKay MJ, Cryns VL. Caspase proteolysis of the cohesin component RAD21 promotes apoptosis. J Biol Chem 2002; 277:16775-16781.

Kamradt MC, Chen F, Cryns VL. The small heat shock protein aB-crystallin negatively regulates cytochrome c- and caspase-8-dependent activation of caspase-3 by inhibiting its autoproteolytic maturation. J Biol Chem 2001; 276:16059-16063.

Byun Y, Chen F, Chang R, Trivedi M, Green KJ, Cryns VL. Caspase cleavage of vimentin disrupts intermediate filaments and promotes apoptosis. Cell Death Differ 2001; 8:443-450.

View Publications by Vince Cryns listed in the National Library of Medicine (PubMed).

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