The ZFHX1A Gene Is Differentially Autoregulated By Its Isoforms

MANAVELLA, P; ROQUEIRO, G; DARLING, DS; CABANILLAS, AM

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

ELSEVIER

Lugar: Amsterdan, The Netherlands; Año: 2007 vol. 360 p. 621 - 626

0006-291X

The Zfhx1a gene expresses two different isoforms; the full length Zfhx1a-1 and a truncated isoform termed Zfhx1a-2 lacking the first exon.  Deletion analysis of the Zfhx1a-1 promoter localized cell-specific repressors, and a proximal G-string that is critically required for transactivation.  Transfection of Zfhx1a-1 cDNA, but not Zfhx1a -2, downregulates Zfhx1a-1 promoter activity.  Mutation of an E2-box disrupted the binding of both Zfhx1a isoforms.  Consistent with this, transfected Zfhx1a-1 does not regulate the transcriptional activity of the E-box mutated Zfhx1a-1 promoter.  Competitive EMSAs and transfection assays show that Zfhx1a-2 can function as a dominant negative isoform since it is able to compete and displace Zfhx1a-1 from its binding site and overcome Zfhx1a-1 induced repression of the Zfhx1a-1 promoter in cells. Hence, the Zfhx1a-1 gene is autoregulated in part by negative feedback on its own promoter which is, in turn, modified by the availability of the negative dominant isoform Zfhx1a-2.