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

Sunil K. Halder, Govindaraj Anumanthan, Ramakoti Maddula, Jason Mann, Anna Chytil, Adriana L. Gonzalez, M. Key Washington, Harold L. Moses, R. Daniel Beauchamp, Pran K. Datta

Research output: Contribution to journalArticle

55 Scopus citations

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-β (TGF-β) 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-β receptors and that synergizes with the inhibitory Smad, Smad7, in the negative regulation of TGF-β-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 p21Cip1, which results in retinoblastoma protein hyperphosphorylation. In addition, we have observed that Smad2/3 phosphorylation, TGF-β-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-β-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-β signaling, reduces ERK activity, increases p21Cip1 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-β-dependent and TGF-β-independent mechanisms, thus demonstrating the oncogenic function of STRAP.

Original languageEnglish (US)
Pages (from-to)6156-6166
Number of pages11
JournalCancer Research
Volume66
Issue number12
DOIs
StatePublished - Jun 15 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Halder, S. K., Anumanthan, G., Maddula, R., Mann, J., Chytil, A., Gonzalez, A. L., Washington, M. K., Moses, H. L., Beauchamp, R. D., & Datta, P. K. (2006). Oncogenic function of a novel WD-domain protein, STRAP, in human carcinogenesis. Cancer Research, 66(12), 6156-6166. https://doi.org/10.1158/0008-5472.CAN-05-3261