Oncogenic function of a novel WD-domain protein, STRAP, in human carcinogenesis.
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.
Halder
Sunil K
SK
Department of Surgery, Vanderbilt-Ingram Cancer Center, TN 37232, USA.
Anumanthan
Govindaraj
G
Maddula
Ramakoti
R
Mann
Jason
J
Chytil
Anna
A
Gonzalez
Adriana L
AL
Washington
M Key
MK
Moses
Harold L
HL
Beauchamp
R Daniel
RD
Datta
Pran K
PK
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002522:Chlorocebus aethiops; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008907:Mink; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009363:Neoplasm Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D016160:Retinoblastoma Protein; C403447:STRAP protein, human; C116758:STRAP protein, mouse; D016212:Transforming Growth Factor beta; D020929:Mitogen-Activated Protein Kinase Kinases