title: Activation of Gαq subunits up-regulates the expression of the tumor suppressor Fhit.
abstract: The tumor suppressor Fhit protein is defective or absent in many tumor cells due to methylation, mutation or deletion of the FHIT gene. Despite numerous attempts to unravel the functions of Fhit, the mechanisms by which the function and expression of Fhit are regulated remain poorly understood. We have recently shown that activated Gαq subunits interact directly with Fhit and enhance its inhibitory effect on cell growth. Here we investigated the regulation of Fhit expression by Gq. Our results showed that Fhit was up-regulated specifically by activating Gα subunits of the Gq subfamily but not by those of the other G protein subfamilies. This up-regulation effect was mediated by a PKC/MEK pathway independent of Src-mediated Fhit Tyr(114) phosphorylation. We further demonstrated that elevated Fhit expression was due to the specific regulation of Fhit protein synthesis in the ribosome by activated Gαq, where the regulations of cap-dependent protein synthesis were apparently not required. Moreover, we showed that activated Gαq could increase cell-cell adhesion through Fhit. These findings provide a possible handle to modulate the level of the Fhit tumor suppressor by manipulating the activity of Gq-coupled receptors.
authors.affiliation: Division of Life Sciences, and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong. Electronic address: hzuo@ust.hk.
authors.forename: Hao
authors.initials: H
authors.lastname: Zuo
authors.forename: Anthony S L
authors.initials: AS
authors.lastname: Chan
authors.forename: Hermann
authors.initials: H
authors.lastname: Ammer
authors.forename: Yung H
authors.initials: YH
authors.lastname: Wong
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020930:MAP Kinase Kinase Kinases; D009363:Neoplasm Proteins; D011493:Protein Kinase C; D000099170:Bis(5'-adenosyl)triphosphatase
keywords: 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester); 4EBP1; Ap(3)A; BAPTA-AM; BK(2)R; CHX; Cell adhesion; DNase; Fhit; G protein; GRPR; IP; MT(1)R; PKC/MEK pathway; PLCβ; Protein synthesis; RGS; TCL; bradykinin type 2 receptor; cycloheximide; deoxyribonuclease; diadenosine 5′,5‴-P1,P3-triphosphate; eIF; eIF4E binding protein 1; eukaryotic initiation factor; gastrin-releasing peptide receptor; immunoprecipitation; melatonin type 1 receptor; phospholipase Cβ; regulator of G protein signaling; total cell lysate; β(2) adrenergic receptor; β(2)AR