title: Signal-induced site specific phosphorylation targets Bcl2 to the proteasome pathway.
abstract: The oncogene derived protein Bcl2 and its family members such as Bcl-xL or Mcl-1 can confer negative control in the pathway of cellular suicide machinery. The reversible phosphorylation of the components in the apoptotic-signaling pathway is likely to be an important regulatory mechanism to control the fate of a cell. Previous reports by others and us demonstrate that phosphorylation of anti-apoptotic proteins such as Bcl2, Bcl-xL or Mcl-1 can regulate their function depending on the apoptotic trigger or cell type. Also, evidence is now accumulating that the ubiquitin proteasome pathway can play an important role in apoptosis. In order to understand whether any cross-talk exists between proteasome and Bcl2 phosphorylation pathways, studies were undertaken employing cell permeable proteasome inhibitors. When proteasomes were inactivated, enhanced accumulation of slower mobility forms of Bcl2 was clearly evident. Due to substitution of the major phosphorylation sites Ser 70, 87 to Ala, no such effect was observed. It is known that in contrary to phospho Bcl2, native Bcl2 (non-phosphoform) is unable to associate with cis-trans peptidyl prolyl isomerase Pin1-a key factor to regulate the fate of phosphoforms of Bcl2 and apoptosis. Thus the enhanced resistance to cell death exhibited by phosphorylation defective mutant Bcl2 might be attributed to its inability to associate with Pin1.
authors.affiliation: Rammelkamp Center for Education and Research, Department of Pharmacology, Ireland Cancer Center, MetroHealth/Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH 44109-1998, USA.
authors.forename: Aruna
authors.initials: A
authors.lastname: Basu
authors.forename: Subrata
authors.initials: S
authors.lastname: Haldar
mesh_terms: D000409:Alanine / Q000378:metabolism; D019943:Amino Acid Substitution; D017209:Apoptosis / Q000502:physiology; D001665:Binding Sites; D002193:Cantharidin / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013379:Substrate Specificity; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019253:Proto-Oncogene Proteins c-bcl-2; D012694:Serine; D010749:Phosphoprotein Phosphatases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; D002193:Cantharidin; D000409:Alanine