Gadd45 beta is a pro-survival factor associated with stress-resistant tumors.
Tumors that acquire resistance against death stimuli constitute a severe problem in the context of cancer therapy. To determine genetic alterations that favor the development of stress-resistant tumors in vivo, we took advantage of polyclonal tumors generated after retroviral infection of newborn Elambda-MYC mice, in which the retroviral integration acts as a mutagen to enhance tumor progression. Tumor cells were cultivated ex vivo and exposed to gamma-irradiation prior to their transplantation into syngenic recipients, thereby providing a strong selective pressure for pro-survival mutations. Secondary tumors developing from stress-resistant tumor stem cells were analysed for retroviral integration sites to reveal candidate genes whose dysregulation confer survival. In addition to the gene encoding the antiapoptotic Bcl-x(L) protein, we identified the gadd45b locus to be a novel common integration site in these tumors, leading to enhanced expression. In accord with a thus far undocumented role of Gadd45beta in tumorigenesis, we showed that NIH3T3 cells overexpressing Gadd45beta form tumors in NOD/SCID mice. Interestingly and differently to other known 'classical' antiapoptotic factors, high Gadd45beta levels did not protect against MYC-, UV- or gamma-irradiation-induced apoptosis, but conferred a strong and specific survival advantage to serum withdrawal.
Engelmann
A
A
Heinrich-Pette-Institut, Hamburg, Germany.
Speidel
D
D
Bornkamm
G W
GW
Deppert
W
W
Stocking
C
C
D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D004195:Disease Models, Animal; D016393:Lymphoma, B-Cell / Q000378:metabolism* / Q000401:mortality / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D018384:Oxidative Stress / Q000502:physiology*; D013534:Survival / Q000502:physiology*; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins