Mxi1-SRalpha: a novel Mxi1 isoform with enhanced transcriptional repression potential.

ABSTRACT

Mxi1 belongs to the Myc/Max/Mad network of proteins that have been implicated in the control of multiple aspects of cellular behavior. Previously, we had reported that the mouse mxi1 gene gives rise to two distinct transcript forms that can encode proteins with dramatically different functional abilities. The Mxi1-SR protein (here termed Mxi1-SRbeta) can interact with Sin3/histone deacetylase and function as a potent transcriptional repressor and growth suppressor, while the Mxi1-WR protein lacks these activities. Here, we describe a new mxi1-derived transcript form (termed mxi1-SRalpha) whose expression is governed by its own promoter, resulting in a spatiotemporally distinct expression profile from that of the highly related mxi1-SRbeta form. Moreover, the Mxi1-SRalpha protein product, with its unique Sin3 interacting domain, has a greater affinity than its Mxi1-SRbeta counterpart for the Sin3 adapter proteins as well as an enhanced potential for transcriptional repression in transient reporter assays. Our identification of this novel Mxi1 isoform that results from alternative 5' exon usage adds an additional layer of complexity to the Mad/Mxi1 family. In addition, our findings warrant re-evaluation of mxi1 expression patterns on the cellular level and its status in human cancer samples, with a renewed focus on the distinct isoforms.