title: The actin-binding protein, actinin alpha 4 (ACTN4), is a nuclear receptor coactivator that promotes proliferation of MCF-7 breast cancer cells.
abstract: Alpha actinins (ACTNs) are known for their ability to modulate cytoskeletal organization and cell motility by cross-linking actin filaments. We show here that ACTN4 harbors a functional LXXLL receptor interaction motif, interacts with nuclear receptors in vitro and in mammalian cells, and potently activates transcription mediated by nuclear receptors. Whereas overexpression of ACTN4 potentiates estrogen receptor α (ERα)-mediated transcription in transient transfection reporter assays, knockdown of ACTN4 decreases it. In contrast, histone deacetylase 7 (HDAC7) inhibits estrogen receptor α (ERα)-mediated transcription. Moreover, the ACTN4 mutant lacking the CaM (calmodulin)-like domain that is required for its interaction with HDAC7 fails to activate transcription by ERα. Chromatin immunoprecipitation (ChIP) assays demonstrate that maximal associations of ACTN4 and HDAC7 with the pS2 promoter are mutually exclusive. Knockdown of ACTN4 significantly decreases the expression of ERα target genes including pS2 and PR and also affects cell proliferation of MCF-7 breast cancer cells with or without hormone, whereas knockdown of HDAC7 exhibits opposite effects. Interestingly, overexpression of wild-type ACTN4, but not the mutants defective in interacting with ERα or HDAC7, results in an increase in pS2 and PR mRNA accumulation in a hormone-dependent manner. In summary, we have identified ACTN4 as a novel, atypical coactivator that regulates transcription networks to control cell growth.
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Simran
authors.initials: S
authors.lastname: Khurana
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Xiwen
authors.initials: X
authors.lastname: Cheng
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Su
authors.forename: Hung-Ying
authors.initials: HY
authors.lastname: Kao
mesh_terms: D000185:Actinin / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D053766:Presenilin-2 / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary
chemical_list: C111453:ACTN4 protein, human; D047628:Estrogen Receptor alpha; D009363:Neoplasm Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D000185:Actinin; C543273:HDAC7 protein, human; D006655:Histone Deacetylases