Publication Date:
2003-01-11
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Xuejun -- Kim, Hyun-Eui -- Shu, Hongjun -- Zhao, Yingming -- Zhang, Haichao -- Kofron, James -- Donnelly, Jennifer -- Burns, Dave -- Ng, Shi-Chung -- Rosenberg, Saul -- Wang, Xiaodong -- GMRO1-57158/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2003 Jan 10;299(5604):223-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12522243" target="_blank"〉PubMed〈/a〉
Keywords:
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
;
Recombinant Proteins/metabolism/pharmacology
;
Signal Transduction
;
Thymosin/*analogs & derivatives/chemistry/isolation &
;
purification/*metabolism/pharmacology
;
Tumor Suppressor Proteins/chemistry/isolation & purification/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
