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Advances in Brief Dpc4 Transcriptional Activation and Dysfunction in Cancer Cells1

By Jia Le Dai, Kenan K. Turnacioglu, Mieke Schutte, Et Al, Contact The Aacr Publications, Jia Le Dai, Kenan K. Turnacioglu, Mieke Schutte, Avrahom Y. Sugar and Scott E. Kern


Dpc4 (Smad4) is implicated in mediation of signals from transforming growth factor (TGF) /! 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 I>!'(-! 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 COOHterminal end with the DNA-binding domain of Dpc4 was evident but was not required to explain the functional impairment produced by MLterminal DPC4 mutations. Both substitution and truncation mutations of the ( '(>()! I-terminal half of DPC4 lacked the ability to regulate transcrip tion 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 activ

Year: 2013
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