%0 Journal Article
%T Theoretical Investigation of the D83V Mutation within the Myocyte-Specific Enhancer Factor-2 Beta and Its Role in Cancer
%A Oleksandr Yakovenko
%A Ryan Morin
%A Ganna Vashchenko
%A Steven J. M. Jones
%J Journal of Theoretical Chemistry
%D 2013
%R 10.1155/2013/313419
%X The D83V mutation in the myocyte-specific enhancer factor-2 beta (MEF2B) gene is frequently observed in lymphomas. Surprisingly, this apparent gain-of-function mutation is within a protein that is involved in the promotion of apoptosis in B cells. To investigate the oncogenic effects of this alteration and explain its predominance over other known loss-of-function mutations of MEF2B, we propose a hypothesis that this mutation influences the dynamic folding of the C-terminal loop of the N-terminal domain of MEF2B. According to our hypothesis, the mutation allows MEF2B to bind promiscuously to a wider variety of gene promoters. A large set of molecular dynamic simulations (MD) was conducted to investigate the effects of D83V mutation in silico and support the hypothesis. 1. Introduction The myocyte-specific enhancer factor-2 (MEF2) family of transcription factors plays an essential role in myogenesis [1, 2] and the regulation of the proapoptotic gene Nur77 [3¨C6]. This family is composed of four members, MEF2A, -B, -C, and -D, which normally function either as homo- or heterodimers [7]. All of these factors recognize the DNA consensus sequence C/TTA(A/T)4TAG/A, which is present within many gene promoters (see [8, 9] and references therein), and consist of a MADS-box containing a N-terminal domain responsible for DNA recognition and dimerization and an as yet uncharacterized C-terminal domain [10]. The sequence differences between the N-terminal domain of MEF2 forms are mainly within the MEF2S subdomain (residues 58¨C95) of the N-terminal domain which is responsible for the determining of DNA binding specificity [11¨C18]. Recently, MEF2B was found to be altered in many B-cell-derived lymphomas [19]. Morin et al. [19] and Youn and Liu [20] proposed a model of MEF2B involvement in the development of lymphomas through dependent signaling downstream of the B-cell receptor. In normal germinal centre B-cells MEF2B binds to the promoter of Nur77, a proapoptotic gene that plays a crucial role in TCR-mediated apoptosis [21¨C23]. However, MEF2B is kept transcriptionally inactive by the suppressor Cabin1 which binds to its N-terminal domain preventing the transcription of Nur77. This repression is calcium-dependent [3, 4]: when enters the cytoplasm in response to B-cell receptor activation, it folds the intrinsically unstructured Calmodulin, which becomes a more preferred partner of Cabin1. Calmodulin in complex with releases Cabin1 from its complex with MEF2B, allowing MEF2B to initiate Nur77 transcription and recruit other activating factors such as HDAC7, HDAC9, and
%U http://www.hindawi.com/journals/jtc/2013/313419/