Human T-lymphotropic virus type-1 p30 alters cell cycle G2 regulation of T lymphocytes to enhance cell survival

Retrovirology. 2007 Jul 16;4:49. doi: 10.1186/1742-4690-4-49.

Abstract

Background: Human T-lymphotropic virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma and is linked to a number of lymphocyte-mediated disorders. HTLV-1 contains both regulatory and accessory genes in four pX open reading frames. pX ORF-II encodes two proteins, p13 and p30, whose roles are still being defined in the virus life cycle and in HTLV-1 virus-host cell interactions. Proviral clones of HTLV-1 with pX ORF-II mutations diminish the ability of the virus to maintain viral loads in vivo. p30 expressed exogenously differentially modulates CREB and Tax-responsive element-mediated transcription through its interaction with CREB-binding protein/p300 and while acting as a repressor of many genes including Tax, in part by blocking tax/rex RNA nuclear export, selectively enhances key gene pathways involved in T-cell signaling/activation.

Results: Herein, we analyzed the role of p30 in cell cycle regulation. Jurkat T-cells transduced with a p30 expressing lentivirus vector accumulated in the G2-M phase of cell cycle. We then analyzed key proteins involved in G2-M checkpoint activation. p30 expression in Jurkat T-cells resulted in an increase in phosphorylation at serine 216 of nuclear cell division cycle 25C (Cdc25C), had enhanced checkpoint kinase 1 (Chk1) serine 345 phosphorylation, reduced expression of polo-like kinase 1 (PLK1), diminished phosphorylation of PLK1 at tyrosine 210 and reduced phosphorylation of Cdc25C at serine 198. Finally, primary human lymphocyte derived cell lines immortalized by a HTLV-1 proviral clone defective in p30 expression were more susceptible to camptothecin induced apoptosis. Collectively these data are consistent with a cell survival role of p30 against genotoxic insults to HTLV-1 infected lymphocytes.

Conclusion: Collectively, our data are the first to indicate that HTLV-1 p30 expression results in activation of the G2-M cell cycle checkpoint, events that would promote early viral spread and T-cell survival.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis / physiology
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell Survival / physiology
  • G2 Phase / genetics*
  • G2 Phase / immunology
  • Genes, pX
  • Human T-lymphotropic virus 1 / genetics
  • Human T-lymphotropic virus 1 / metabolism
  • Human T-lymphotropic virus 1 / physiology*
  • Humans
  • Jurkat Cells
  • Oligonucleotide Array Sequence Analysis / methods
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / physiology
  • Transduction, Genetic
  • Transfection
  • Viral Core Proteins / biosynthesis
  • Viral Core Proteins / genetics
  • Viral Core Proteins / physiology*
  • cdc25 Phosphatases / metabolism

Substances

  • Cell Cycle Proteins
  • Viral Core Proteins
  • CDC25C protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • cdc25 Phosphatases