A Novel Interaction between FLICE-Associated Huge Protein (FLASH) and E2A Regulates Cell Proliferation and Cellular Senescence via Tumor Necrosis Factor (TNF)-Alpha-p21WAF1/CIP1 Axis.
A Novel Interaction between FLICE-Associated Huge Protein (FLASH) and E2A Regulates Cell Proliferation and Cellular Senescence via Tumor Necrosis Factor (TNF)-Alpha-p21WAF1/CIP1 Axis.
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DOI：
10.1371/journal.pone.0133205
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Abe H
中科院分区：
文献类型：
--
作者：
Hirano T;Murakami T;Ono H;Sakurai A;Tominaga T;Takahashi T;Nagai K;Doi T;Abe H
细胞增殖失调与许多疾病的病理生理学有关。细胞衰老限制癌细胞的增殖，防止肿瘤发生并限制组织损伤。然而，细胞衰老在增殖性肾炎中的作用尚未确定。实验性大鼠肾炎的增殖峰值与肾小球中 E2A 表达的峰值一致。同时，E12（E2A编码的转录因子）本身并不促进系膜细胞（MC）的增殖。我们通过酵母双杂交筛选，将 caspase-8 结合蛋白 FLICE 相关巨蛋白 (FLASH) 鉴定为新型 E2A 结合伴侣。 FLASH 的敲低抑制了 MC 的增殖。 E2A 的敲低可部分逆转这种抑制作用。此外，FLASH的敲低诱导了细胞周期蛋白依赖性激酶抑制剂p21WAF1/CIP1（p21）的表达，但不影响p53的表达。此外，在没有 FLASH 的情况下，E12 和 E47 的过表达在 MC 中诱导 p21，但不诱导 p53。我们还证明，在大鼠增殖性肾小球肾炎的系膜区，E2A 和 p21 在增殖高峰表达后，FLASH 显着诱导。此外，我们发现 FLASH 通过与 E12 相互作用负向调节细胞衰老。我们还证明 FLASH 参与 TNF-α 诱导的 p21 表达。这些结果表明，E2A 和 FLASH 的功能相互作用通过调节实验性肾小球肾炎中的 p21 表达，在细胞增殖和细胞衰老中发挥重要作用。
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.