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

Halder SK, Anumanthan G, Maddula R, Mann J, Chytil A, Gonzalez AL, Washington MK, Moses HL, Beauchamp RD, Datta PK
Cancer Res. 2006 66 (12): 6156-66

PMID: 16778189 · DOI:10.1158/0008-5472.CAN-05-3261

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.

MeSH Terms (22)

Adaptor Proteins, Signal Transducing Animals Cell Transformation, Neoplastic Chlorocebus aethiops Colorectal Neoplasms COS Cells 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 Neoplasm Proteins NIH 3T3 Cells Oncogenes Phosphorylation Proteins Retinoblastoma Protein Transforming Growth Factor beta

Connections (4)

This publication is referenced by other Labnodes entities: