SUMO modification of Stra13 is required for repression of cyclin D1 expression and cellular growth arrest.
Stra13, a basic helix-loop-helix (bHLH) transcription factor is involved in myriad biological functions including cellular growth arrest, differentiation and senescence. However, the mechanisms by which its transcriptional activity and function are regulated remain unclear. In this study, we provide evidence that post-translational modification of Stra13 by Small Ubiquitin-like Modifier (SUMO) dramatically potentiates its ability to transcriptionally repress cyclin D1 and mediate G(1) cell cycle arrest in fibroblast cells. Mutation of SUMO acceptor lysines 159 and 279 located in the C-terminal repression domain has no impact on nuclear localization; however, it abrogates association with the co-repressor histone deacetylase 1 (HDAC1), attenuates repression of cyclin D1, and prevents Stra13-mediated growth suppression. HDAC1, which promotes cellular proliferation and cell cycle progression, antagonizes Stra13 sumoylation-dependent growth arrest. Our results uncover an unidentified regulatory axis between Stra13 and HDAC1 in progression through the G(1)/S phase of the cell cycle, and provide new mechanistic insights into regulation of Stra13-mediated transcriptional repression by sumoylation.
Department of Physiology, National University of Singapore, Singapore, Singapore.
Yaju
Y
Wang
Vinay Kumar
VK
Rao
Wai Kay
WK
Kok
Dijendra Nath
DN
Roy
Sumita
S
Sethi
Belinda Mei Tze
BM
Ling
Martin Beng Huat
MB
Lee
Reshma
R
Taneja
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D019556:COS Cells; D002453:Cell Cycle; D002470:Cell Survival; D002522:Chlorocebus aethiops; D019938:Cyclin D1 / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D025842:SUMO-1 Protein / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D019938:Cyclin D1; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT; D025842:SUMO-1 Protein; C491539:Bhlhe40 protein, mouse; C551977:CENPX protein, human; C484745:PIAS3 protein, human; C109279:Pias3 protein, mouse