Hematopoietic cells from Gadd45a- and Gadd45b-deficient mice are sensitized to genotoxic-stress-induced apoptosis.
Gadd45a, gadd45b and gadd45g (Gadd45/MyD118/CR6) are genes that are rapidly induced by genotoxic stress. However, the exact function of Gadd45 proteins in the response of mammalian cells to genotoxic stress is unclear. Here, advantage was taken of gadd45a- and gadd45b-deficient mice to determine the role gadd45a and gadd45b play in the response of bone marrow (BM) cells to genotoxic stress. BM cells from gadd45a- and gadd45b-deficient mice were observed to be more sensitive to ultraviolet radiation chemotherapy (UVC), VP-16 and daunorubicin (DNR)-induced apoptosis compared to wild-type (wt) cells. The increased apoptosis in gadd45a- and gadd45b-deficient cells was evident also by enhanced activation of caspase-3 and poly-ADP-ribose polymerase cleavage and decreased expression of c-inhibitor of apoptotic protein-1, Bcl-2, Bcl-xL compared to wt cells. Reintroduction of gadd45 into gadd45-deficient BM cells restored the wt apoptotic phenotype. Both gadd45a- and gadd45b-deficient BM cells also displayed defective G2/M arrest following exposure to UVC and VP-16, but not to DNR, indicating the existence of different G2/M checkpoints that are either dependent or independent of gadd45. Taken together, these findings identify gadd45a and gadd45b as anti-apoptotic genes that increase the survival of hematopoietic cells following exposure to UV radiation and certain anticancer drugs.
Gupta
Mamta
M
Fels Institute of Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Gupta
Shiv K
SK
Balliet
Arthur G
AG
Hollander
Mary Christine
MC
Fornace
Albert J
AJ
Hoffman
Barbara
B
Liebermann
Dan A
DA
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage; D003630:Daunorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D012190:Retroviridae / Q000235:genetics; D014466:Ultraviolet Rays; D014467:Ultraviolet Therapy; D000097642:GADD45 Proteins
D017304:Annexin A5; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D003630:Daunorubicin; D005047:Etoposide; D047908:Intracellular Signaling Peptides and Proteins; D000097642:GADD45 Proteins