Flash Controls of Proliferation and Senescence through p21
Hirano, Takahiro University of Tokushima
村上, 太一 University of Tokushima KAKEN研究者をさがす
小野, 広幸 University of Tokushima
櫻井, 明子 University of Tokushima 徳島大学 教育研究者総覧 KAKEN研究者をさがす
冨永, 辰也 University of Tokushima 徳島大学 教育研究者総覧 KAKEN研究者をさがす
髙橋, 利和 University of Tokushima
長井, 幸二郎 University of Tokushima KAKEN研究者をさがす
土井, 俊夫 University of Tokushima 徳島大学 教育研究者総覧 KAKEN研究者をさがす
安部, 秀斉 University of Tokushima 徳島大学 教育研究者総覧 KAKEN研究者をさがす
Dysregulation of the cell proliferation has been implicated in the pathophysiology of a number of diseases. Cellular senescence limits proliferation of cancer cells, preventing tumorigenesis and restricting tissue damage. However, the role of cellular senescence in proliferative nephritis has not been determined. The proliferative peak in experimental rat nephritis coincided with a peak in E2A expression in the glomeruli. Meanwhile, E12 (an E2A-encoded transcription factor) did not promote proliferation of Mesangial cells (MCs) by itself. We identified caspase-8-binding protein FLICE-associated huge protein (FLASH) as a novel E2A-binding partner by using a yeast two-hybrid screening. Knockdown of FLASH suppressed proliferation of MCs. This inhibitory effect was partially reversed by the knockdown of E2A. In addition, the knockdown of FLASH induced cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) expression, but did not affect p53 expression. Furthermore, overexpression of E12 and E47 induced p21, but not p53 in MCs, in the absence of FLASH. We also demonstrated that E2A and p21 expression at the peak of proliferation was followed by significant induction of FLASH in mesangial areas in rat proliferative glomerulonephritis. Moreover, we revealed that FLASH negatively regulates cellular senescence via the interaction with E12. We also demonstrated that FLASH is involved in the TNF-α-induced p21 expressions. These results suggest that the functional interaction of E2A and FLASH play an important role in cell proliferation and cellular senescence via regulation of p21 expression in experimental glomerulonephritis.
© 2015 Hirano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License(https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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