Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway

  • Science. 2003 Jan 10;299(5604):223-6. doi: 10.1126/science.1076807.
Xuejun Jiang  1 ,  Hyun-Eui Kim ,  Hongjun Shu ,  Yingming Zhao ,  Haichao Zhang ,  James Kofron ,  Jennifer Donnelly ,  Dave Burns ,  Shi-Chung Ng ,  Saul Rosenberg ,  Xiaodong Wang
Affiliations
  • 1. Howard Hughes Medical Institute, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
PMID: 12522243 DOI: 10.1126/science.1076807
Abstract

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.

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