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

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-initi...

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Veröffentlicht in:Science (American Association for the Advancement of Science) 2003-01, Vol.299 (5604), p.223
Hauptverfasser: Jiang, Xuejun, Kim, Hyun-Eui, Shu, Hongjun, Zhao, Yingming, Zhang, Haichao, Kofron, James, Donnelly, Jennifer, Burns, Dave, Ng, Shi-chung, Rosenberg, Saul, Wang, Xiaodong
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Sprache:eng
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Zusammenfassung: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.
ISSN:0036-8075