This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Montgomery, E. Articles by Kern, S. E. Search for Related Content PubMed PubMed Citation Articles by Montgomery, E. Articles by Kern, S. E.

(American Journal of Pathology. 2001;158:537-542.)
© 2001 American Society for Investigative Pathology

Regular Article

Nuclear Localization of Dpc4 (Madh4, Smad4) in Colorectal Carcinomas and Relation to Mismatch Repair/Transforming Growth Factor-{beta} Receptor Defects

Elizabeth Montgomery^*, Michael Goggins, Shibin Zhou, Pedram Argani^*, Robb E. Wilentz^*, Manju Kaushal^*, Susan Booker, Katharine Romans^*, Parul Bhargava^*, Ralph H. Hruban^* and Scott E. Kern

From the Departments of Pathology,^*
Oncology,
and Gastroenterology,
The Johns Hopkins Medical Institutions, Baltimore, Maryland

The tumor-suppressor protein Dpc4 (Smad4, Madh4) regulates gene expression. On binding of an extracellular ligand of the extensive transforming growth factor (TGF) superfamily to its cognate receptor complex, latent cytoplasmic Dpc4 is activated and translocated into the nucleus to function as part of various DNA-binding transcriptional activator complexes. The most relevant ligand/receptor pair to control the tumor suppressive function of Dpc4 remains uncertain, but is usually assumed to be TGF-{beta} and its heteromeric receptor. We exploited a fortuitous experiment of nature to directly test this hypothesis: the TGF-{beta} type II receptor gene is inactivated by mutation in nearly all colorectal carcinomas having microsatellite instability, as seen in hereditary nonpolyposis colorectal cancer (HNPCC) and in sporadic medullary colorectal cancers. Using a specific and sensitive immunohistochemical label for Dpc4, we examined nuclear localization of Dpc4 in 13 HNPCC, six medullary, and 41 sporadic nonmedullary colorectal carcinomas. In agreement with published rates, two (5%) of 41 sporadic tumors showed complete loss of Dpc4 protein, indicative of genetic inactivation. All 13 HNPCC and six medullary tumors had intact cytoplasmic and nuclear Dpc4 localization. The TGFBR2 gene was sequenced in three of the cancers from patients with HNPCC, and all of these harbored inactivating mutations. The specificity of the immunohistochemical assay was demonstrated in xenograft tumors of syngeneic cell lines that differed in DPC4 genetic status because of an engineered gene knockout. Thus, nuclear localization of Dpc4 can be maintained in cells with inactivated TGF-{beta} type II receptors, suggesting the persistence of tumor-suppressive action of an upstream signaling input, most likely a ligand/receptor complex distinct from TGF-{beta}. Identification of the relevant input would be expected to have implications for the understanding of tumorigenesis and the design of rational biological therapy.

This article has been cited by other articles:

				P. Mehlen and E. R. Fearon Role of the Dependence Receptor DCC in Colorectal Cancer Pathogenesis J. Clin. Oncol., August 15, 2004; 22(16): 3420 - 3428. [Abstract] [Full Text] [PDF]

				D. B. Alexander, H. Ichikawa, J. F. Bechberger, V. Valiunas, M. Ohki, C. C. G. Naus, T. Kunimoto, H. Tsuda, W. T. Miller, and G. S. Goldberg Normal Cells Control the Growth of Neighboring Transformed Cells Independent of Gap Junctional Communication and Src Activity Cancer Res., February 15, 2004; 64(4): 1347 - 1358. [Abstract] [Full Text] [PDF]