Oncogenic function of a novel WD-domain protein, STRAP, in human carcinogenesis.

Academic Article

Abstract

  • The development and progression of malignancies is a complex multistage process that involves the contribution of a number of genes giving growth advantage to cells when transformed. The role of transforming growth factor-beta (TGF-beta) in carcinogenesis is complex with tumor-suppressor or prooncogenic activities depending on the cell type and the stage of the disease. We have previously reported the identification of a novel WD-domain protein, STRAP, that associates with both TGF-beta receptors and that synergizes with the inhibitory Smad, Smad7, in the negative regulation of TGF-beta-induced transcription. Here, we show that STRAP is ubiquitously expressed and is localized in both cytoplasm and nucleus. STRAP is up-regulated in 60% colon and in 78% lung carcinomas. Stable expression of STRAP results in activation of mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and in down-regulation of the cyclin-dependent kinase inhibitor p21(Cip1), which results in retinoblastoma protein hyperphosphorylation. In addition, we have observed that Smad2/3 phosphorylation, TGF-beta-mediated transcription, and growth inhibition are induced in STRAP-knockout mouse embryonic fibroblasts compared with wild-type cells. Ectopic expression of STRAP in A549 lung adenocarcinoma cell line inhibits TGF-beta-induced growth inhibition and enhances anchorage-independent growth of these cells. Moreover, overexpression of STRAP increases tumorigenicity in athymic nude mice. Knockdown of endogenous STRAP by small interfering RNA increases TGF-beta signaling, reduces ERK activity, increases p21(Cip1) expression, and decreases tumorigenicity. Taken together, these results suggest that up-regulation of STRAP in human cancers may provide growth advantage to tumor cells via TGF-beta-dependent and TGF-beta-independent mechanisms, thus demonstrating the oncogenic function of STRAP.
  • Published In

  • Cancer Research  Journal
  • Keywords

  • Adaptor Proteins, Signal Transducing, Animals, COS Cells, Cell Transformation, Neoplastic, Cercopithecus aethiops, Colorectal Neoplasms, Cyclin-Dependent Kinase Inhibitor p21, Enzyme Activation, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, MAP Kinase Signaling System, Mice, Mink, Mitogen-Activated Protein Kinase Kinases, NIH 3T3 Cells, Neoplasm Proteins, Oncogenes, Phosphorylation, Proteins, Retinoblastoma Protein, Transforming Growth Factor beta
  • Digital Object Identifier (doi)

    Pubmed Id

  • 18772364
  • Author List

  • Halder SK; Anumanthan G; Maddula R; Mann J; Chytil A; Gonzalez AL; Washington MK; Moses HL; Beauchamp RD; Datta PK
  • Start Page

  • 6156
  • End Page

  • 6166
  • Volume

  • 66
  • Issue

  • 12