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Science 299 (5604): 223-226

Copyright © 2003 by the American Association for the Advancement of Science

Distinctive Roles of PHAP Proteins and Prothymosin-alpha in a Death Regulatory Pathway

Xuejun Jiang,12 Hyun-Eui Kim,12 Hongjun Shu,2 Yingming Zhao,2 Haichao Zhang,3 James Kofron,3 Jennifer Donnelly,3 Dave Burns,3 Shi-chung Ng,3 Saul Rosenberg,3 Xiaodong Wang12*

A small molecule, alpha -(trichloromethyl)-4-pyridineethanol (PETCM), was identified by high-throughput screening as an activator of caspase-3 in extracts of a panel of cancer cells. PETCM was used in combination with biochemical fractionation to identify a pathway that regulates mitochondria-initiated caspase activation. This pathway consists of tumor suppressor putative HLA-DR-associated proteins (PHAP) and oncoprotein prothymosin-alpha (ProT). PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation. PETCM relieved ProT inhibition and allowed apoptosome formation at a physiological concentration of deoxyadenosine triphosphate. Elimination of ProT expression by RNA interference sensitized cells to ultraviolet irradiation-induced apoptosis and negated the requirement of PETCM for caspase activation. Thus, this chemical-biological combinatory approach has revealed the regulatory roles of oncoprotein ProT and tumor suppressor PHAP in apoptosis.

1 Howard Hughes Medical Institute,
2 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3 Abbott Laboratories, D-460, AP10-LL, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
*   To whom correspondence should be addressed. E-mail: xwang{at}biochem.swmed.edu



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