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

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.
AuthorsXuejun Jiang, Hyun-Eui Kim, Hongjun Shu, Yingming Zhao, Haichao Zhang, James Kofron, Jennifer Donnelly, Dave Burns, Shi-Chung Ng, Saul Rosenberg, Xiaodong Wang
JournalScience (New York, N.Y.) (Science) Vol. 299 Issue 5604 Pg. 223-6 (Jan 10 2003) ISSN: 1095-9203 [Electronic] United States
PMID12522243 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • ANP32A protein, human
  • ANP32B protein, human
  • APAF1 protein, human
  • Apoptotic Protease-Activating Factor 1
  • Cell Extracts
  • Cytochrome c Group
  • Deoxyadenine Nucleotides
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Nuclear Proteins
  • Protein Precursors
  • Proteins
  • Pyridines
  • RNA-Binding Proteins
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • alpha-(trichloromethyl)-4-pyridineethanol
  • prothymosin alpha
  • Thymosin
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9
  • Caspases
  • 2'-deoxyadenosine triphosphate
Topics
  • Amino Acid Sequence
  • Apoptosis
  • Apoptotic Protease-Activating Factor 1
  • Caspase 3
  • Caspase 9
  • Caspases (metabolism)
  • Cell Extracts
  • Cytochrome c Group (metabolism)
  • Deoxyadenine Nucleotides (metabolism, pharmacology)
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mitochondria (metabolism)
  • Molecular Sequence Data
  • Neuropeptides
  • Nuclear Proteins (chemistry, isolation & purification, metabolism, pharmacology)
  • Protein Precursors (chemistry, isolation & purification, metabolism, pharmacology)
  • Proteins (chemistry, isolation & purification, metabolism, pharmacology)
  • Pyridines (chemistry, pharmacology)
  • RNA Interference
  • RNA-Binding Proteins
  • Recombinant Proteins (metabolism, pharmacology)
  • Signal Transduction
  • Thymosin (analogs & derivatives, chemistry, isolation & purification, metabolism, pharmacology)
  • Tumor Suppressor Proteins (chemistry, isolation & purification, metabolism)

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