CD44 negatively regulates apoptosis in murine colonic epithelium via the mitochondrial pathway.
Regulation of epithelial cell proliferation and apoptosis are important determinants of colonic crypt homeostasis, and their dysregulations are key features of colon cancer. In this study, we investigated whether CD44, an adhesion protein overexpressed in colon cancer, plays a role in colonocyte proliferation and apoptosis, and the molecular mechanisms involved in these processes. Using a CD44 knockout mouse model devoid of a gross phenotype, we found that CD44 null colonocytes have alterations at the ultrastructural and molecular levels. Mitochondria in CD44 null colonocytes at the top of the crypt have disrupted cristae. The ratio of anti-apoptotic Bcl-xl to pro-apoptotic Bak was shifted toward apoptosis in CD44 null colon due to decreased Bcl-xl expression. Caspase 9 was upregulated and active in CD44 null colon. Its expression shifted from a location restricted to the top of the control crypts to the whole crypt axis in CD44 null colon. Caspase 3 was also activated in CD44 null colon suggesting that CD44 null colonocytes are apoptotic via the intrinsic pathway. Cell cycle regulators, cyclin A, p21, and pRb protein were abrogated in CD44 null mice. Overall, CD44 negatively regulates apoptosis via the mitochondrial pathway in the colonic epithelium through the regulators/effectors of cell cycle and apoptosis.
Lakshman
Minalini
M
Department of Laboratory Medicine and Pathobiology, St. Michael's Hospital and University of Toronto, Toronto, ON, Canada M5B 1W8.
Subramaniam
Venkateswaran
V
Jothy
Serge
S
D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion; D002453:Cell Cycle / Q000502:physiology; D003106:Colon / Q000276:immunology / Q000378:metabolism*; D019925:Cyclin A / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004848:Epithelium / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006720:Homozygote; D018960:Hyaluronan Receptors / Q000235:genetics / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
C494773:Bak1 protein, mouse; C494812:Bcl2l1 protein, mouse; C493957:Cdkn1a protein, mouse; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018960:Hyaluronan Receptors; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases