SIGNALING BY TYROSINE KINASES NEGATIVELY REGULATES THE INTERACTION BETWEEN TRANSCRIPTION FACTORS AND SMRT (SILENCING MEDIATOR OF RETINOIC ACID AND THYROID-HORMONE RECEPTOR) COREPRESSOR

Nuclear hormone receptors are hormone-regulated transcription factors that bind to specific sites on DNA and modulate the expression of adja cent target genes. Many nuclear hormone receptors display bimodal tran scriptional properties; thyroid hormone receptors, for example, typica lly repress target gene expression in the absence of hormone, but acti vate target gene expression in the presence of hormone. The ability to repress is closely linked to the ability of the ape-receptor to physi cally bind to auxiliary corepressor proteins denoted SMRT (silencing m ediator of retinoic acid and thyroid hormone receptor) and N-CoR (nucl ear receptor corepressor), which, in turn, help mediate the actual mol ecular events involved in transcriptional silencing. We report here th at repression by thyroid hormone receptors can be regulated not only b y cognate hormone, but also by certain tyrosine kinase signal transduc tion pathways, such as that represented by the epidermal growth factor -receptor. Activation of tyrosine kinase signaling leads to inhibition of T3R-mediated repression with relatively little effect on activatio n. These effects appear to be mediated by a kinase-initiated disruptio n of the ability of T3R to interact with SMRT corepressor. Intriguingl y, tyrosine kinase signaling similarly disrupted the interactions of S MRT with v-Erb A, with retinoic acid receptors, and with PLZF, a nonre ceptor transcriptional repressor. We conclude that tyrosine kinase sig naling exerts potentially important regulatory effects on transcriptio nal silencing mediated by a variety of transcription factors that oper ate through the SMRT corepressor complex.