TTC5 is required to prevent apoptosis of acute myeloid leukemia stem cells.
Affiliation
Cancer Research UK Leukaemia Biology Laboratory, Paterson Institute for Cancer Research, The University of Manchester, Manchester, UK.Issue Date
2013
Metadata
Show full item recordAbstract
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.Citation
TTC5 is required to prevent apoptosis of acute myeloid leukemia stem cells. 2013, 4:e573 Cell Death DisJournal
Cell Death & DiseaseDOI
10.1038/cddis.2013.107PubMed ID
23559008Type
ArticleLanguage
enISSN
2041-4889ae974a485f413a2113503eed53cd6c53
10.1038/cddis.2013.107
Scopus Count
Collections
Related articles
- A histone acetyltransferase p300 inhibitor C646 induces cell cycle arrest and apoptosis selectively in AML1-ETO-positive AML cells.
- Authors: Gao XN, Lin J, Ning QY, Gao L, Yao YS, Zhou JH, Li YH, Wang LL, Yu L
- Issue date: 2013
- A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival.
- Authors: Jude JG, Spencer GJ, Huang X, Somerville TDD, Jones DR, Divecha N, Somervaille TCP
- Issue date: 2015 Mar 5
- Evaluation of the Role of p53 Tumour Suppressor Posttranslational Modifications and TTC5 Cofactor in Lung Cancer.
- Authors: Alhebshi H, Tian K, Patnaik L, Taylor R, Bezecny P, Hall C, Muller PAJ, Safari N, Creamer DPM, Demonacos C, Mutti L, Bittar MN, Krstic-Demonacos M
- Issue date: 2021 Dec 7
- c-Myc suppresses miR-451⊣YWTAZ/AKT axis via recruiting HDAC3 in acute myeloid leukemia.
- Authors: Su R, Gong JN, Chen MT, Song L, Shen C, Zhang XH, Yin XL, Ning HM, Liu B, Wang F, Ma YN, Zhao HL, Yu J, Zhang JW
- Issue date: 2016 Nov 22
- Inhibition of the intrinsic but not the extrinsic apoptosis pathway accelerates and drives MYC-driven tumorigenesis towards acute myeloid leukemia.
- Authors: Högstrand K, Hejll E, Sander B, Rozell B, Larsson LG, Grandien A
- Issue date: 2012