Regulation of the tumor marker Fascin by the viral oncoprotein Tax of human T-cell leukemia virus type 1 (HTLV-1) depends on promoter activation and on a promoter-independent mechanism

Virology. 2015 Nov;485:481-91. doi: 10.1016/j.virol.2015.08.025. Epub 2015 Sep 9.

Abstract

Adult T-cell leukemia/lymphoma is a highly infiltrative neoplasia of CD4(+) T-lymphocytes that occurs in about 5% of carriers infected with the deltaretrovirus human T-cell leukemia virus type 1 (HTLV-1). The viral oncoprotein Tax perturbs cellular signaling pathways leading to upregulation of host cell factors, amongst them the actin-bundling protein Fascin, an invasion marker of several types of cancer. However, transcriptional regulation of Fascin by Tax is poorly understood. In this study, we identified a triple mode of transcriptional induction of Fascin by Tax, which requires (1) NF-κB-dependent promoter activation, (2) a Tax-responsive region in the Fascin promoter, and (3) a promoter-independent mechanism sensitive to the Src family kinase inhibitor PP2. Thus, Tax regulates Fascin by a multitude of signals. Beyond, using Tax-expressing and virus-transformed lymphocytes as a model system, our study is the first to identify the invasion marker Fascin as a novel target of PP2, an inhibitor of metastasis.

Keywords: ATL; Fascin; HTLV-1; NF‐kappa B (NF‐KB); Oncogene; PP2; Promoter; Tax; Transcription regulation; Tumor virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Transformation, Viral
  • Gene Expression Regulation* / drug effects
  • Gene Products, tax / metabolism*
  • Human T-lymphotropic virus 1 / genetics
  • Human T-lymphotropic virus 1 / metabolism*
  • Humans
  • Microfilament Proteins / genetics*
  • Microfilament Proteins / metabolism
  • Models, Biological
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic*
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • T-Lymphocytes / virology
  • Transcriptional Activation
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism

Substances

  • Carrier Proteins
  • Gene Products, tax
  • Microfilament Proteins
  • NF-kappa B
  • Protein Kinase Inhibitors
  • fascin
  • src-Family Kinases