부산대학교 도서관

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 Eλ-MYC mice, in which the retroviral integration acts as a mutagen to enhance tumor progression. Tumor cells were cultivated ex vivo and exposed to γ-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-xL 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 Gadd45β in tumorigenesis, we showed that NIH3T3 cells overexpressing Gadd45β form tumors in NOD/SCID mice. Interestingly and differently to other known ‘classical’ antiapoptotic factors, high Gadd45β levels did not protect against MYC-, UV- or γ-irradiation-induced apoptosis, but conferred a strong and specific survival advantage to serum withdrawal.Oncogene (2008) 27, 1429–1438; doi:10.1038/sj.onc.1210772; published online 24 September 2007 [ABSTRACT FROM AUTHOR]