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Departments of Oncology [M. S., S. E. K.] and Pathology [J. L. D., K. K. T., A. Y. S., S. E. K.], The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196
Dpc4 (Smad4) is implicated in mediation of signals from transforming growth factor (TGF) ß and related ligands, and wild-type Dpc4 mediates TGF-ß-stimulated gene transcription at specific DNA sequences bound by Dpc4 [Smad binding element (SBE)]. We characterized panels of DPC4 tumor mutations and cancer cell lines. Amino acid substitutions within the NH2-terminal third of Dpc4 weakened or ablated SBE-mediated gene regulation by a disruption of DNA binding. An interaction of the COOH-terminal end with the DNA-binding domain of Dpc4 was evident but was not required to explain the functional impairment produced by NH2-terminal DPC4 mutations. Both substitution and truncation mutations of the COOH-terminal half of DPC4 lacked the ability to regulate transcription while retaining the sequence-specific DNA-binding function, but through differing mechanisms. A modular domain to redistribute Dpc4 to the nuclear compartment allowed SBE-mediated transcriptional activation in a cell line having a TGF-ß receptor defect and was sufficient to restore SBE-mediated transactivation ability to COOH-terminal DPC4 missense mutants. Cells harboring DPC4 alterations had a universal impairment of the TGF-ß-stimulated SBE transcriptional response. These studies identify the loss of SBE-mediated gene regulation as a uniform outcome of the selection for DPC4 alterations during tumorigenesis. They raise the possibility of restoration of some Dpc4-associated transcriptional events in cancer cells through the targeted redistribution of wild-type and some missense mutant forms of Dpc4 to the nucleus.
1 This work was supported by NIH Grant CA68228.
2 To whom requests for reprints should be addressed, at 632 Ross Building, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196. Phone: (410) 614-3314; Fax: (410) 614-0671; E-mail: sk@welchlink.welch.jhu.edu.
Received 7/13/98. Accepted 8/31/98.
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