title: TTC5 is required to prevent apoptosis of acute myeloid leukemia stem cells.
abstract: Using a screening strategy, we identified the tetratricopeptide repeat (TPR) motif protein, Tetratricopeptide repeat domain 5 (TTC5, also known as stress responsive activator of p300 or Strap) as required for the survival of human acute myeloid leukemia (AML) cells. TTC5 is a stress-inducible transcription cofactor known to interact directly with the histone acetyltransferase EP300 to augment the TP53 response. Knockdown (KD) of TTC5 induced apoptosis of both murine and human AML cells, with concomitant loss of clonogenic and leukemia-initiating potential; KD of EP300 elicited a similar phenotype. Consistent with the physical interaction of TTC5 and EP300, the onset of apoptosis following KD of either gene was preceded by reduced expression of BCL2 and increased expression of pro-apoptotic genes. Forced expression of BCL2 blocked apoptosis and partially rescued the clonogenic potential of AML cells following TTC5 KD. KD of both genes also led to the accumulation of MYC, an acetylation target of EP300, and the form of MYC that accumulated exhibited relative hypoacetylation at K148 and K157, residues targeted by EP300. In view of the ability of excess cellular MYC to sensitize cells to apoptosis, our data suggest a model whereby TTC5 and EP300 cooperate to prevent excessive accumulation of MYC in AML cells and their sensitization to cell death. They further reveal a hitherto unappreciated role for TTC5 in leukemic hematopoiesis.
authors.affiliation: Cancer Research UK Leukaemia Biology Laboratory, Paterson Institute for Cancer Research, The University of Manchester, Manchester, UK.
authors.forename: J T
authors.initials: JT
authors.lastname: Lynch
authors.forename: T D D
authors.initials: TD
authors.lastname: Somerville
authors.forename: G J
authors.initials: GJ
authors.lastname: Spencer
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.forename: T C P
authors.initials: TC
authors.lastname: Somervaille
mesh_terms: D000107:Acetylation; D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006410:Hematopoiesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C495901:TP53 protein, human; C557280:TTC5 protein, human
references.citation: Genes Dev. 1999 Jun 1;13(11):1367-81
references.pmid: 10364155
references.citation: Nature. 2012 Mar 28;483(7391):603-7
references.pmid: 22460905
references.citation: Br J Haematol. 2003 Mar;120(5):876-86
references.pmid: 12614225
references.citation: Cell Stem Cell. 2009 Feb 6;4(2):129-40
references.pmid: 19200802
references.citation: Eur J Immunol. 1988 Jan;18(1):97-104
references.pmid: 2831066
references.citation: Nat Cell Biol. 2008 Dec;10(12):1431-9
references.pmid: 19011621
references.citation: Mol Cell Biol. 2005 Dec;25(23):10220-34
references.pmid: 16287840
references.citation: Cell. 1992 Apr 3;69(1):119-28
references.pmid: 1555236
references.citation: Cancer Cell. 2012 Apr 17;21(4):473-87
references.pmid: 22464800
references.citation: Nat Rev Cancer. 2012 Sep;12(9):599-612
references.pmid: 22898539
references.citation: Blood. 2000 Feb 1;95(3):745-55
references.pmid: 10648382
references.citation: Nat Cell Biol. 2004 Oct;6(10):968-76
references.pmid: 15448695
references.citation: EMBO Rep. 2008 Dec;9(12):1222-9
references.pmid: 18833288
references.citation: Cancer Cell. 2006 Oct;10(4):257-68
references.pmid: 17045204
references.citation: Lancet. 2006 Nov 25;368(9550):1894-907
references.pmid: 17126723
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14789-94
references.pmid: 12397173
references.citation: Cell Stress Chaperones. 2011 Jul;16(4):353-67
references.pmid: 21153002
references.citation: Mol Endocrinol. 2011 Jan;25(1):58-71
references.pmid: 21147850
references.citation: EMBO Rep. 2008 Jul;9(7):662-9
references.pmid: 18451878
references.citation: Mol Cell. 2001 Jul;8(1):71-84
references.pmid: 11511361