Role of caspase 9 in activation of HTLV-1 LTR expression by DNA damaging agents

Ammar Abou-Kandil, Rachel Chamias, Mahmoud Huleihel, W. T. Godbey, Mordechai Aboud

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Adult T-cell leukemia (ATL) is caused by HTLV-I. The viral Tax oncoprotein plays a central role in initiating the process to ATL. However, after infection HTLV-1 enters into latency, during which virus gene expression is very low, so that the level of Tax is likely insufficient for exerting its oncogenic activities. Therefore only 5% of the infected individuals may develop ATL several decades after infection. It is assumed that the transition from latency to ATL development requires at least a temporary activation of the latent virus in order to elevate Tax to its oncogenic threshold. We have previously found that DNA damaging agents, which usually induce apoptosis, can also activate the viral long terminal repeats (LTR) and that the anti-apoptosis Bcl-2 protein not only inhibits the induction of apoptosis but concomitantly prevents their LTR activation effect. Therefore, the present study was designed to identify the factor that while participating in the apoptotic cascade acts also to activate the viral LTR. For this purpose we employed ectopic vectors expressing these apoptotic factors together with potent shRNAs against each of them and anti caspase peptide inhibitors. We have found that in addition to its function as initiator of the mitochondrial apoptotic cascade, caspase 9 can acts also as an executer which among other non-apoptotic functions it forms an Sp1-p53 complex that activates the LTR by binding to an Sp1 recognition site residing in the LTR. This finding can help in designing effective preventing strategies against ATL development in clinically latent HTLV-1 carriers.

Original languageEnglish
Pages (from-to)3337-3345
Number of pages9
JournalCell Cycle
Volume10
Issue number19
DOIs
StatePublished - 1 Oct 2011

Keywords

  • ATL
  • Caspase 9
  • Complex
  • HTLV-1 LTR
  • Latent HTLV-1
  • MOMP
  • Mitochondrial apoptotic cascade
  • Sp1-p53

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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