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Research Paper

TGFβ modulates PTEN expression independently of SMAD signaling for growth proliferation in colon cancer cells

Jimmy Y.C. Chow, Jennifer A. Cabral, Jessica Chang and John M. Carethers

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Signaling pathways enabling transforming growth factor-beta (TGFβ)’s conversion from a tumor suppressor to a tumor promoter are not well characterized. TGFβ utilizes intracellular SMADs to mediate growth suppression; however, TGFβ-induced proliferative pathways may become more apparent when SMAD signaling is abrogated. Here, we determined regulation of the tumor suppressor PTEN by TGFβ utilizing SMAD4-null colon cancer cells. TGFβ downregulated PTEN mRNA and simultaneously induced growth proliferation. TGFβ also induced both SMAD2 and SMAD3 nuclear translocation, but only triggered SMAD2-specific transcriptional activity in the absence of SMAD4. Interference of SMAD2 with DN-SMAD2 enhanced TGFβ-induced cell proliferation, but downregulation of PTEN expression by TGFβ was unaffected. TGFβ increased PI3K tyrosine phosphorylation, and inhibition of PI3K pharmacologically or by DN-p85 transfection reversed both TGFβ-induced PTEN suppression and TGFβ-induced cell proliferation. Thus, TGFβ activates PI3K to downregulate PTEN for enhancement of cell proliferation that is independent of SMAD proteins.

Authors

Jimmy Y.C. Chow

University of California, San Diego, California

Jennifer A. Cabral

University of California, San Diego, California

Jessica Chang

University of California, San Diego, California

John M. Carethers

University of California, San Diego, California/VA San Diego Healthcare System

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If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.