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Oncogenic Function of a Novel WD-Domain Protein, STRAP, in Human Carcinogenesis

Departments of ¹ Surgery and ² Cancer Biology, Vanderbilt-Ingram Cancer Center; and Departments of ³ Medicine and ⁴ Medical Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee

Requests for reprints: Pran K. Datta, Surgical Oncology Division, Department of Surgery, Vanderbilt University School of Medicine, 1161 21st Avenue South, A-3310C MCN, Nashville, TN 37232. Phone: 615-343-1280; Fax: 615-343-1355; E-mail: pran.datta{at}vanderbilt.edu.

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-ß (TGF-ß) 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-ß receptors and that synergizes with the inhibitory Smad, Smad7, in the negative regulation of TGF-ß–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-ß–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-ß–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-ß 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-ß–dependent and TGF-ß–independent mechanisms, thus demonstrating the oncogenic function of STRAP. (Cancer Res 2006; 66(12): 6156-66)

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