Anticancer-drug-induced apoptotic cell death in leukemia cells is associated with proteolysis of beta-catenin.
beta-Catenin is a known regulator of cell-cell adhesion and transcriptional regulation. However, the role of beta-catenin and its regulation in non-adherent cells has not been examined. Therefore, we examined the role and fate of beta-catenin during hematopoietic cell apoptosis using Jurkat T-acute lymphoblastic and U937 acute myeloblastic leukemia cells. The results presented here demonstrate that the treatment of Jurkat cells with the apoptosis inducers anti-Fas, TRAIL, staurosporine, and etoposide induces proteolytic fragments of beta-catenin, as did TRAIL and staurosporine in U937 cells. In Jurkat cells, beta-catenin was cleaved at both the N- and C-terminal after anti-Fas addition. Cleavage of intact beta-catenin was completely inhibited by caspase selective protease inhibitors. There was a clear accumulation of the large proteolytic fragment in Jurkat cells treated with lactacystin or N-acetyl-leucyl leucyl-methioninal (ALLM). These results suggest that both the proteasome and calpain may recognize the large beta-catenin fragment as a substrate for further degradation. Densitometric analysis demonstrated that the loss of intact beta-catenin was more rapid in the cell nucleus (beta-catenin T1/2 of approximately 1.5h in cytoplasm and 0.5h in nucleus). Down-regulation of beta-catenin-associated transcription was an early event in response to anti-Fas. These results suggest that beta-catenin plays a role in promoting Jurkat survival.
Department of Pathology, College of Oriental Medicine, Wonkwang University, Iksan, Chonbuk, South Korea.
Sang Gu
SG
Hwang
Hyung Chul
HC
Lee
Jane B
JB
Trepel
Byung Hun
BH
Jeon
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002154:Calpain / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000502:physiology*; D053222:Fas Ligand Protein; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000502:physiology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D020298:U937 Cells / Q000187:drug effects* / Q000378:metabolism; D051176:beta Catenin; D019014:fas Receptor / Q000276:immunology / Q000502:physiology
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D015853:Cysteine Proteinase Inhibitors; D003598:Cytoskeletal Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D051176:beta Catenin; D019014:fas Receptor; D002154:Calpain; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex