Abstract
Yin Yang 1 (YY1) is a member of the GLI-Krüppel class of DNA and RNA binding transcription factors that can either activate or repress gene expression during cell growth, differentiation, and embryogenesis. Although much is known about YY1 interacting proteins and the target promoters regulated by YY1, much less is known about YY1 regulation through post-translational modifications. In this study we show that YY1 is tyrosine-phosphorylated in multiple cell types. Using a combination of pharmacological inhibition, kinase overexpression, and kinase knock-out studies, we demonstrate that YY1 is a target of multiple Src family kinases in vitro and in vivo. Moreover, we have identified multiple sites of YY1 phosphorylation and analyzed the effect of phosphorylation on the activity of YY1-responsive retroviral and cellular promoters. Phosphorylation of tyrosine 383 interferes with DNA and RNA binding, leading to the down-regulation of YY1 activity. Finally, we provide the first evidence that YY1 is a downstream target of epidermal growth factor receptor signaling in vivo. Taken together, the identification of YY1 as a target of Src family kinases provide key insights into the inhibitory role of tyrosine kinases in modulating YY1 activity.
Highlights
Yin Yang 1 is a transcription factor capable of activating or repressing its target genes, depending on context and cofactors
Yin Yang 1 (YY1) Is Tyrosine-phosphorylated in Multiple Cell Types—To address whether YY1 is a target of tyrosine phosphorylation in vivo, Jurkat cells were treated with pervanadate to inhibit endogenous tyrosine phosphatases, and YY1 phosphorylation was assayed by immunoprecipitation and Western blotting using an anti-phosphotyrosine antibody
To investigate the sites of Src family kinase-induced YY1 phosphorylation in vivo, we introduced mutations altering each of the six tyrosine to nonphosphorylatable phenylalanine residues in the protein (Tyr to Phe) and asked whether single mutations affected the phosphorylation of YY1 in Src family kinase-overexpressing cells
Summary
Yin Yang 1 is a transcription factor capable of activating or repressing its target genes, depending on context and cofactors. Yin Yang 1 (YY1) is a member of the GLI-Krüppel class of DNA and RNA binding transcription factors that can either activate or repress gene expression during cell growth, differentiation, and embryogenesis. In Xenopus oocytes, YY1 has been demonstrated to associate with structurally divergent RNA species [5], raising the possibility that YY1 can bind both DNA and RNA Highlighting this dual binding property, YY1 was shown to tether Xist, a noncoding RNA (lncRNA), to DNA regions on the X chromosome, leading to X chromosome inactivation in maternal cells [6]. In this study we provide evidence that YY1 is a target of tyrosine phosphorylation in various cell types by members of the Src family kinases. We show that phosphorylation of YY1 in its DNA binding domain interferes with its ability to bind DNA or RNA, thereby down-regulating its ability to repress or activate gene expression from known retroviral and cellular promoters. Our findings provide insights into the control of YY1mediated transcription by cellular tyrosine kinases
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