TGF-beta signaling pathway inactivation and cell cycle deregulation in the development of gastric cancer: role of the beta-spectrin, ELF.

We have shown that loss of ELF, a stem cell adaptor protein, disrupts TGF-beta signaling through Smad3 and Smad4 localization. Notably elf(+/-)/smad4(+/-) mice develop gastric cancer presenting this as an important model for analyzing molecular event in gastric carcinogenesis. To gain further insight into the functional role of ELF in gastric cancer suppression, we carried out a detailed characterization of cell cycle events leading to gastric tumorigenesis. elf(-/-) cells and elf(+/-)/smad4(+/-) mice demonstrate a marked alteration of cell cycle regulators, such as Cdk4, K-Ras, and p21. Levels of Cdk4 increased compared to normal controls, suggesting loss of ELF results in functional abnormalities in cell cycle regulation. We further demonstrate that the elf(-/-) MEFs show a disruption of G1/S cell cycle transition and a significant reduction in senescence. Thus, in response to ELF deficiency, the abnormalities of G1/S checkpoint and senescence contribute their increment of susceptibility to malignant transformation.