title: HEXIM1 induces differentiation of human pluripotent stem cells.
abstract: Hexamethylene bisacetamide inducible protein 1 (HEXIM1) is best known as the inhibitor of positive transcription elongation factor b (P-TEFb), which is composed of cyclin-dependent kinase 9 (CDK9)/cyclin T1. P-TEFb is an essential regulator for the transcriptional elongation by RNA polymerase II. A genome-wide study using human embryonic stem cells shows that most mRNA synthesis is regulated at the stage of transcription elongation, suggesting a possible role for P-TEFb/HEXIM1 in the gene regulation of stem cells. In this report, we detected a marked increase in HEXIM1 protein levels in the differentiated human pluripotent stem cells (hPSCs) induced by LY294002 treatment. Since no changes in CDK9 and cyclin T1 were observed in the LY294002-treated cells, increased levels of HEXIM1 might lead to inhibition of P-TEFb activity. However, treatment with a potent P-TEFb inhibiting compound, flavopiridol, failed to induce hPSC differentiation, ruling out the possible requirement for P-TEFb kinase activity in hPSC differentiation. Conversely, differentiation was observed when hPSCs were incubated with hexamethylene bisacetamide, a HEXIM1 inducing reagent. The involvement of HEXIM1 in the regulation of hPSCs was further supported when overexpression of HEXIM1 concomitantly induced hPSC differentiation. Collectively, our study demonstrates a novel role of HEXIM1 in regulating hPSC fate through a P-TEFb-independent pathway.
authors: Stem Cell Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore, Singapore.
authors: Vanessa
authors: V
authors: Ding
authors: Qiao Jing
authors: QJ
authors: Lew
authors: Kai Ling
authors: KL
authors: Chu
authors: Subaashini
authors: S
authors: Natarajan
authors: Vikneswari
authors: V
authors: Rajasegaran
authors: Meera
authors: M
authors: Gurumurthy
authors: Andre B H
authors: AB
authors: Choo
authors: Sheng-Hao
authors: SH
authors: Chao
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D056906:Cyclin T / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D004475:Ectoderm / Q000166:cytology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008648:Mesoderm / Q000166:cytology; D010880:Piperidines / Q000494:pharmacology; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D042925:Positive Transcriptional Elongation Factor B / Q000037:antagonists & inhibitors / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000081:Acetamides; D015415:Biomarkers; D056906:Cyclin T; D005419:Flavonoids; C476123:HEXIM1 protein, human; D010880:Piperidines; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C077990:alvocidib; D042925:Positive Transcriptional Elongation Factor B; D042863:Cyclin-Dependent Kinase 9; C014026:hexamethylene bisacetamide
references: J Cell Mol Med. 2011 Nov;15(11):2539-51
references: 21883888
references: Mol Cell. 2008 Apr 11;30(1):7-10
references: 18406322
references: Cell Cycle. 2011 Jun 15;10(12):1978-87
references: 21558800
references: Nat Biotechnol. 2000 Apr;18(4):399-404
references: 10748519
references: J Biotechnol. 2006 Mar 9;122(1):130-41
references: 16233925
references: J Embryol Exp Morphol. 1978 Feb;43:289-313
references: 75937
references: J Cell Physiol. 2010 Nov;225(2):417-28
references: 20506199
references: Nature. 2001 Nov 15;414(6861):317-22
references: 11713532
references: Dev Biol. 2000 Nov 1;227(1):133-45
references: 11076682
references: Mol Cell Biol. 2003 Jul;23(14):4859-69
references: 12832472
references: J Biol Chem. 2004 Nov 12;279(46):48063-70
references: 15328362
references: Nat Biotechnol. 2001 Dec;19(12):1134-40
references: 11731782
references: Nat Biotechnol. 2006 Nov;24(11):1392-401
references: 17053790
references: Cancer Res. 2003 Aug 15;63(16):5151-8
references: 12941847
references: Cell Cycle. 2008 Dec;7(23):3759-67
references: 19029824
references: J Cell Sci. 2010 Nov 1;123(Pt 21):3789-95
references: 20940258
references: Circ Res. 2003 Jul 11;93(1):32-9
references: 12791707
references: Stem Cell Res. 2012 Mar;8(2):259-73
references: 22265745
references: J Biol Chem. 2012 Oct 19;287(43):36443-54
references: 22948151
references: Biotechnol Lett. 2006 Apr;28(7):491-5
references: 16614931
references: J Mol Biol. 2008 Apr 25;378(2):302-17
references: 18371977
references: Oncogene. 2005 Aug 25;24(36):5576-88
references: 15940264
references: Science. 1998 Nov 6;282(5391):1145-7
references: 9804556
references: Dev Biol. 1994 Mar;162(1):181-94
references: 8125186
references: J Biol Chem. 2001 Aug 24;276(34):31793-9
references: 11431468
references: Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3834-8
references: 8170997
references: Differentiation. 1993 Jan;52(2):129-37
references: 8097171
references: PLoS Pathog. 2007 Oct 12;3(10):1459-69
references: 17937499
references: Mol Cell Biol. 2003 Feb;23(3):831-41
references: 12529389
references: Genes Cells. 2003 Feb;8(2):95-107
references: 12581153
references: Mol Cell. 2006 Aug 4;23(3):297-305
references: 16885020
references: Cell Cycle. 2004 Dec;3(12):1537-42
references: 15539947
references: J Biol Chem. 2005 May 13;280(19):19115-26
references: 15699019
references: Cancer Res. 1977 Feb;37(2):440-4
references: 264411
references: J Mol Biol. 2010 Jan 8;395(1):28-41
references: 19883659
references: Cell Cycle. 2009 Jul 15;8(14):2247-54
references: 19617712
references: Stem Cells. 2008 Jun;26(6):1454-63
references: 18356574
references: Dev Dyn. 1995 Jul;203(3):363-76
references: 8589433
references: Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8555-60
references: 15941832
references: J Biol Chem. 2005 Jul 1;280(26):24968-77
references: 15855166
references: Cell. 1998 Oct 30;95(3):379-91
references: 9814708
references: Cell. 2007 Jul 13;130(1):77-88
references: 17632057
references: Development. 1998 May;125(10):1967-78
references: 9550729
references: Nat Genet. 2007 Dec;39(12):1512-6
references: 17994019
references: Nat Genet. 2007 Dec;39(12):1507-11
references: 17994021
references: J Biol Chem. 2000 Sep 15;275(37):28345-8
references: 10906320
references: Nature. 2001 Nov 15;414(6861):322-5
references: 11713533
references: Stem Cells Dev. 2008 Aug;17(4):825-36
references: 18788934
references: Am J Physiol Heart Circ Physiol. 2003 Dec;285(6):H2355-63
references: 14613910
references: Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10251-4
references: 7937935
references: Stem Cells. 2007 Jun;25(6):1511-20
references: 17332508
references: Cell. 2007 Nov 30;131(5):861-72
references: 18035408
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Cell Cycle. 2007 Aug 1;6(15):1856-63
references: 17671421
references: Genes Dev. 1998 Mar 1;12(5):755-62
references: 9499409
references: Mol Cell Biol. 1993 Apr;13(4):2235-46
references: 8455608
references: Diabetes. 2001 Aug;50(8):1691-7
references: 11473026
references: Mol Cell. 2003 Oct;12(4):971-82
references: 14580347
references: Science. 2007 Dec 21;318(5858):1917-20
references: 18029452
references: J Biol Chem. 1999 Dec 3;274(49):34527-30
references: 10574912