Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 344, Issue 4, Pages 1216-1223Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2006.03.236
Keywords
ELF; gastric cancer; Smad4; cell cycle; senescence
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Funding
- NCI NIH HHS [R01 CA106614A, R01 CA106614] Funding Source: Medline
- NIDDK NIH HHS [R01 DK58637, R01 DK056111, R01 DK56111] Funding Source: Medline
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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 G(1)/S cell cycle transition and a significant reduction in senescence. Thus, in response to ELF deficiency, the abnormalities of G(1)/S checkpoint and senescence contribute their increment of susceptibility to malignant transformation. (c) 2006 Published by Elsevier Inc.
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