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Transforming Growth Factor-ß-induced Growth Inhibition in a Smad4 Mutant Colon Adenoma Cell Line¹

Howard Hughes Medical Institute [S. P. F., J. D. L., J. M., B. V., S. M.], Department of Medicine [S. E. S., J. K. V. W., S. M.], and Ireland Cancer Center [J. K. V. W., S. M.], Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106; Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [J. M.]; Genetics Program, Boston University School of Medicine, Boston, Massachusetts 02118 [S. T.]; and The Johns Hopkins Oncology Center, Baltimore, Maryland 21231 [S. T., K. W. K., B. V.]

Transforming growth factor-ß (TGF-ß) inhibits growth and induces apoptosis of colon epithelial cells. Binding of TGF-ß to its receptor induces phosphorylation of the Smad proteins Smad2 and Smad3, which then form heteromeric complexes with Smad4, translocate to the nucleus, and activate gene transcription. Smad4 function has been considered an obligate requirement for TGF-ß signaling, and Smad4 mutations present in some cancers have been considered sufficient to inactivate TGF-ß signaling. In this work, we describe studies with a nontransformed human colon epithelial cell line that is mutant for Smad4 but remains growth-inhibited by TGF-ß. The colon cell line VACO-235 has lost one of its Smad4 alleles via a chromosome 18q deletion. The remaining allele bears two missense point mutations located in regions important for Smad4 trimer formation, which is thought necessary for Smad4 function. As expected, pSBE4-BV/Luc, a Smad4-activated transcriptional reporter, was inactive in VACO-235. Nonetheless, VACO-235 demonstrated 80% growth inhibition in response to TGF-ß, as well as retention of some TGF-ß-mediated activation of the p3TP-Lux transcriptional reporter. Transient transfection of the VACO-235 Smad4 mutant allele into a Smad4-null cell line confirmed that this allele is functionally inactive as assayed by both the pSBE4-BV and p3TP-Lux reporters. The simplest explanation of these results is that there is a non-Smad4-dependent pathway for TGF-ß-mediated signaling and growth inhibition in VACO-235 cells.

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