title: Transforming growth-interacting factor (TGIF) regulates proliferation and differentiation of human myeloid leukemia cells.
abstract: Transforming growth-interacting factor (TGIF) is a homeobox transcriptional repressor that has been implicated in holoprosencephaly and various types of cancer. TGIF is expressed in hematopoietic stem cells and modulates TGF-beta and retinoic acid (RA) signaling, both of which play an important role in hematopoiesis. We recently reported that TGIF's levels correlate inversely with survival in patients with acute myelogenous leukemia. Here we present the first direct evidence of a role for TGIF in myelopoiesis. We used short hairpin RNA interference to define the effects of TGIF knockdown on proliferation and differentiation of myeloid leukemia-derived cell lines. Decreased TGIF expression resulted in reduced proliferation and differentiation and lower expression of CEBPbeta, CEBPepsilon, PU.1 and RUNX1, key myeloid transcription factors. Furthermore, TGF-beta signaling was increased and RA signaling was decreased. Further insights into the molecular basis of TGIF's effects were provided by a genome-wide chromatin immunoprecipitation-based elucidation of TGIF target genes. Together, these data suggest that TGIF has an important role myelopoiesis and may regulate the balance between proliferation and differentiation. Reduced TGIF expression could tip the balance toward quiescence thus providing progenitor as well as hematopoietic stem cells protection from anti-cycle agents.
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, United States. rizwan.hamid@vanderbilt.edu
authors.forename: Rizwan
authors.initials: R
authors.lastname: Hamid
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Brandt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology; D051379:Mice; D038042:Myelopoiesis / Q000502:physiology*; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D012097:Repressor Proteins; C097504:TGIF1 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014212:Tretinoin
references.citation: Cell. 1999 Apr 2;97(1):29-39
references.pmid: 10199400
references.citation: Nat Genet. 1999 Jun;22(2):196-8
references.pmid: 10369266
references.citation: Blood. 1997 Mar 15;89(6):2113-21
references.pmid: 9058734
references.citation: Leukemia. 2002 Oct;16(10):1896-905
references.pmid: 12357341
references.citation: BMC Genomics. 2007 May 31;8:139
references.pmid: 17540029
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):749-54
references.pmid: 15640349
references.citation: Nat Rev Immunol. 2007 Feb;7(2):105-17
references.pmid: 17259967
references.citation: Nat Biotechnol. 1997 Sep;15(9):871-5
references.pmid: 9306402
references.citation: Mol Cell Biol. 2006 Jun;26(11):4302-10
references.pmid: 16705179
references.citation: Exp Hematol. 1999 Sep;27(9):1355-67
references.pmid: 10480426
references.citation: Immunity. 2007 Jun;26(6):726-40
references.pmid: 17582345
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13424-9
references.pmid: 14581620
references.citation: J Cell Sci. 2000 Feb;113 ( Pt 3):383-90
references.pmid: 10639326
references.citation: Cell. 1993 Sep 24;74(6):1009-20
references.pmid: 8402878
references.citation: Cell. 2005 May 6;121(3):335-48
references.pmid: 15882617
references.citation: Science. 2000 Jun 2;288(5471):1635-40
references.pmid: 10834841
references.citation: J Lipid Res. 2008 Jun;49(6):1224-34
references.pmid: 18310014
references.citation: Biochem Biophys Res Commun. 1998 Nov 18;252(2):368-72
references.pmid: 9826536
references.citation: Mol Cancer Res. 2003 Jun;1(8):619-30
references.pmid: 12805409
references.citation: Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13187-92
references.pmid: 9371821
references.citation: J Biochem Mol Biol. 2002 Jan 31;35(1):47-53
references.pmid: 16248969
references.citation: J Immunol. 1990 Mar 1;144(5):1767-76
references.pmid: 2407783
references.citation: Dev Biol. 2003 Aug 15;260(2):404-13
references.pmid: 12921741
references.citation: Blood. 2006 Apr 15;107(8):3330-8
references.pmid: 16352814
references.citation: Oncogene. 2008 Oct 20;27(48):6299-312
references.pmid: 18931695
references.citation: Cell Physiol Biochem. 2009;23(1-3):157-64
references.pmid: 19255510
references.citation: Nat Genet. 1998 Oct;20(2):180-3
references.pmid: 9771712
references.citation: Cell Growth Differ. 2001 Sep;12(9):457-63
references.pmid: 11571228
references.citation: Cell. 2006 Mar 24;124(6):1283-98
references.pmid: 16564017
references.citation: Mol Ther. 2000 Aug;2(2):170-6
references.pmid: 10947945
references.citation: J Biol Chem. 1999 Dec 24;274(52):37105-10
references.pmid: 10601270
references.citation: Science. 1996 Apr 12;272(5259):263-7
references.pmid: 8602510
references.citation: J Biol Regul Homeost Agents. 2003 Jan-Mar;17(1):46-65
references.pmid: 12757021
references.citation: Exp Hematol. 2005 Sep;33(9):1055-61
references.pmid: 16140154
references.citation: J Biol Chem. 1995 Dec 29;270(52):31178-88
references.pmid: 8537382
references.citation: PPAR Res. 2007;2007:87934
references.pmid: 17846663
references.citation: Mol Oncol. 2009 Dec;3(5-6):451-63
references.pmid: 19699159
references.citation: Oncogene. 2008 Apr 7;27(16):2289-99
references.pmid: 18391971
references.citation: Curr Protoc Immunol. 2005 Jul;Chapter 22:Unit 22F.5
references.pmid: 18432952
references.citation: Leukemia. 2003 Sep;17(9):1731-7
references.pmid: 12970772
references.citation: Oncogene. 2005 Aug 29;24(37):5676-92
references.pmid: 16123801
references.citation: Hum Genet. 2002 May;110(5):422-8
references.pmid: 12073012
references.citation: Mol Cell. 2006 Aug;23(4):547-59
references.pmid: 16916642
references.citation: Blood. 1996 Jul 1;88(1):82-8
references.pmid: 8704205
references.citation: Nat Genet. 1996 Nov;14(3):353-6
references.pmid: 8896571
references.citation: Oncogene. 2001 Oct 29;20(49):7178-85
references.pmid: 11704846
references.citation: Hum Genet. 2002 Apr;110(4):297-301
references.pmid: 11941477
references.citation: Mol Cell Biol. 2006 Feb;26(3):990-1001
references.pmid: 16428452
references.citation: Biochim Biophys Acta. 2008 May;1779(5):347-55
references.pmid: 18455519
references.citation: Br J Haematol. 1997 Dec;99(4):951-8
references.pmid: 9432049
references.citation: RNA. 2003 Apr;9(4):493-501
references.pmid: 12649500
references.citation: J Cell Physiol. 1989 Oct;141(1):65-73
references.pmid: 2789227
references.citation: EMBO J. 2008 Jul 9;27(13):1804-15
references.pmid: 18511908
references.citation: Blood. 1999 Nov 1;94(9):3141-50
references.pmid: 10556201