title: 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.
abstract: 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.
authors.affiliation: Department of Nephrology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Department of Nephrology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Murakami
authors.affiliation: Department of Nephrology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ono
authors.affiliation: Department of Nephrology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Sakurai
authors.affiliation: Department of Nephrology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tominaga
authors.affiliation: Department of Nephrology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Nephrology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Nagai
authors.affiliation: Department of Nephrology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Doi
authors.affiliation: Department of Nephrology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Abe
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C119301:Casp8ap2 protein, mouse