Regulation of BCL11B by post-translational modifications Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/df65vb38x

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  • Bcl11b (B-cell lymphoma/leukemia 11b), also known as Ctip2 (Chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2), is a C2H2 zinc finger transcriptional regulatory protein, which is an essential protein for post-natal life in the mouse and plays crucial roles in the development, and presumably function, of several organ systems, including the central nervous, immune, craniofacial formation and cutaneous/skin systems. Moreover, inactivation of Bcl11b has been implicated in the etiology of lymphoid malignancies, suggesting that Bcl11b may function as a tumor suppressor. Bcl11b was originally identified as a protein that interacted directly with the orphan nuclear receptor COUP-TF2. Later studies revealed that this C2H2 zinc finger protein can bind DNA directly in a COUP-independent manner, and it has been studied mostly as a transcription repressor. In T cells, gene repression mediated by Bcl11b involves the recruitment of class I HDACs, HDAC1 and HDAC2, within the context of the Nu It has become evident that post-translational modifications (PTMs) play essential roles in modulating activity of transcription regulators. By sensing extracellular signals, cells initiate a series of signaling cascades, which eventually transduce to transcription factors by PTMs, leading to changes of gene expression profile. cleosome Remodeling and Deacetylation (NuRD) complex. The hypothesis that Bcl11b functions as a transcriptional repressor has been supported by transcriptome analyses in mouse T cells and human neuroblastoma cells. However, approximately one-third of the genes that were dysregulated in the double positive (DP) cells of Bcl11b-null mice were down-regulated relative to control T cells, suggesting that Bcl11b may act as a transcriptional activator in some promoter and/or cell contexts. We have also found that Bcl11b functions as a transcriptional activator in a promoter context-dependent manner. However, how Bcl11b and its transcription regulatory activity is regulated still remain largely unknown. Here, we study the reversible, covalent modification of Bcl11b by phosphorylation and small ubiquitin-like modifier (SUMO). We have identifiedK679 and K877 as the two major Bcl11b SUMOylation sites by mutagenesis study. We have shown that phosphorylation and SUMOylation of Bcl11b are likely mutually exclusive processes, and phosphorylation of Bcl11b inhibits its SUMOylation by promoting the recruitment of SUMO specific protease SENP1. To study the function of Bcl11b SUMOylation, we fused SUMO1 to the amino terminus of Bcl11b. This generated a form of Bcl11b that was constitutively sumoylated without the complications of indirect effects associated with overexpression of SUMO1. Our data presented using the constitutive SUMO-Bcl11b demonstrated that SUMOylation compromises the transcription repression mediated by Bcl11b. Interestingly, when Bcl11b is fused to a cleavable form of SUMO, Bcl11b is targeted to ubiquitination pathway and it is degraded through proteasome machinery, suggesting that SUMOylation targets Bcl11b to the ubiquitination-proteasome machinery and deSUMOylation of SUMO conjugated Bcl11b is required for this process. These results described herein provide a framework for understanding the mechanisms underlying the transcription regulatory activities of Bcl11b, and how Bcl11b is regulated by post-translational modifications, including phosphorylation and SUMOylation. These studies may contribute to a better understanding of the molecular and cellular basis for Bcl11b function in vivo.
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