Tumor promotion by Mdm2 splice variants unable to bind p53.
The Mdm2 oncoprotein physically associates with p53 and antagonizes its tumor suppressor functions. Previous studies indicate that some tumors express alternatively or aberrantly spliced Mdm2 variants that are unable to bind p53, but whether these actively contribute to carcinogenesis or are a byproduct of cancer progression has been unclear. In this study, we examined the ability of full-length Mdm2 and several tumor-derived splice variants to modulate tumor development in E micro -myc transgenic mice. We report that several tumor-derived Mdm2 splice variants promote tumorigenesis in a manner that is comparable with full-length Mdm2. Our results imply that the current paradigm for understanding Mdm2 action during oncogenesis is incomplete, and its splice variants contribute to human cancer.
Fridman
Jordan S
JS
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Hernando
Eva
E
Hemann
Michael T
MT
de Stanchina
Elisa
E
Cordon-Cardo
Carlos
C
Lowe
Scott W
SW
D017398:Alternative Splicing; D000818:Animals; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins; D011485:Protein Binding; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018076:DNA, Complementary; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2