Endoplasmic reticulum stress initiates apoptotic death induced by STI571 inhibition of p210 bcr-abl tyrosine kinase.
The endoplasmic reticulum (ER) is the site where proteins destined to either secretion or different subcellular compartments assemble and the major storage of intracellular Ca(2+). The ER stress resulting from a variety of toxic insults leads to apoptosis. Here, we showed that the apoptotic death triggered by STI571, an inhibitor of the p210 bcr-abl tyrosine kinase, in murine myeloid progenitors transducing the p210 bcr-abl tyrosine kinase of Chronic Myeloid Leukemia (CML) proceeds from ER stress. The Bcl-2 dowmodulation and inactivation induced by the binding to its antagonist: Bad, the release of caspase 12 from the ER membranes in its active form and of Ca(2+) from the ER pool addressed towards ER a sensor of STI571-induced pro-apoptotic signal.
Pattacini
Laura
L
Istituto di Ematologia e Oncologia Medica, Lorenzo e Ariosto Seràgnoli, Università di Bologna-Medical School, S. Orsola Hospital, Via Massarenti 9, Bologna 40138, Italy.
Mancini
Manuela
M
Mazzacurati
Lucia
L
Brusa
Gianluca
G
Benvenuti
Michela
M
Martinelli
Giovanni
G
Baccarani
Michele
M
Santucci
Maria Alessandra
MA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D002118:Calcium / Q000378:metabolism; D053454:Caspase 12; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D015536:Down-Regulation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D013696:Temperature; D014161:Transduction, Genetic
D001549:Benzamides; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C506440:Casp12 protein, mouse; D053454:Caspase 12; D020169:Caspases; D002118:Calcium