Abstract
In previous studies, we have reported that phospholipase C (PLC)-β1 plays a crucial role in myogenic differentiation and we determined the importance of its catalytic activity for the initiation of this process. Here we define the effectors that take part to its signaling pathway. We show that the Inositol Polyphosphate Multikinase (IPMK) is able to promote myogenic differentiation since its overexpression determines the up-regulation of several myogenic markers. Moreover, we demonstrate that IPMK activates the same cyclin D3 promoter region targeted by PLC-β1 and that IPMK-induced promoter activation relies upon c-jun binding to the promoter, as we have shown previously for PLC-β1. Furthermore, our data shows that IPMK overexpression causes an increase in β-catenin translocation and accumulation to the nuclei of differentiating myoblasts resulting in higher MyoD activation. Finally, we describe that PLC-β1 overexpression determines too an increase in β-catenin translocation and that PLC-β1, IPMK and β-catenin are mediators of the same signaling pathway since their overexpression results in cyclin D3 and myosin heavy chain (MYH) induction.
Highlights
Myogenic differentiation is a well-defined and highly ordered process that involves several distinct and complex events: myoblasts proliferation, cell-cycle withdrawal, cell migration, alignment and fusion into multinucleated myotubes [1]
Inositol Polyphosphate Multikinase (IPMK) is involved in phospholipase C (PLC)-β1-dependent signaling since it activates the same cyclin D3 promoter region targeted by PLC-β1, and we show that the promoter activation depends upon c-jun binding
We have described the relevance of PLC-β1-dependent signaling pathway in myogenic differentiation since PLC-β1 expression increases during differentiation [14] but its overexpression is able to induce the differentiation process
Summary
Myogenic differentiation is a well-defined and highly ordered process that involves several distinct and complex events: myoblasts proliferation, cell-cycle withdrawal, cell migration, alignment and fusion into multinucleated myotubes [1]. The regulation of these processes requires the activation of several transcription factors belonging to two main families: the MRFs (Myogenic Regulatory Factors) and MEF2 (Myocyte Enhancer Factor-2) family [2]. Myf and MyoD are expressed early in cell committed to differentiation while myogenin and MRF4 are expressed when cells enter terminal differentiation [6,7,8]. The activation of differentiation process leads to the expression of late differentiation markers such as troponin, tropomyosin and myosin heavy and light chains that are among the downstream targets of MRFs and MEF2 family
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