MacNicol MC et al. (2015), Functional Integration of mRNA Translational Co...

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Biomolecules 2015 Jun 26;53:1580-99. doi: 10.3390/biom5031580.

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Functional Integration of mRNA Translational Control Programs.

MacNicol MC , Cragle CE , Arumugam K , Fosso B , Pesole G , MacNicol AM .

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Regulated mRNA translation plays a key role in control of cell cycle progression in a variety of physiological and pathological processes, including in the self-renewal and survival of stem cells and cancer stem cells. While targeting mRNA translation presents an attractive strategy for control of aberrant cell cycle progression, mRNA translation is an underdeveloped therapeutic target. Regulated mRNAs are typically controlled through interaction with multiple RNA binding proteins (RBPs) but the mechanisms by which the functions of distinct RBPs bound to a common target mRNA are coordinated are poorly understood. The challenge now is to gain insight into these mechanisms of coordination and to identify the molecular mediators that integrate multiple, often conflicting, inputs. A first step includes the identification of altered mRNA ribonucleoprotein complex components that assemble on mRNAs bound by multiple, distinct RBPs compared to those recruited by individual RBPs. This review builds upon our knowledge of combinatorial control of mRNA translation during the maturation of oocytes from Xenopus laevis, to address molecular strategies that may mediate RBP diplomacy and conflict resolution for coordinated control of mRNA translational output. Continued study of regulated ribonucleoprotein complex dynamics promises valuable new insights into mRNA translational control and may suggest novel therapeutic strategies for the treatment of disease.

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	Figure 1. Coordinated control of mRNA subsets. The four cytoplasmic mRNAs shown (labeled with numbered white squares) form three RNA regulons that are determined by the binding of RBPs (labeled R1, R2 and R3) to specific sequence elements within the mRNAs. These interactions lead to co-regulation of distinct mRNAs within each RNA regulon (adapted from [35]). The fate of co-regulated, co-occupied mRNAs is less clear when mRNAs possess binding sites for multiple RBPs with antagonistic action (e.g., bound by both R1 and R2 concurrently (mRNA 3) or R2 and R3 (mRNA 2).
	Figure 2. mRNA translational diplomacyâintegration of multiple regulatory inputs. (A) When an mRNA is regulated by a single RBP (R1, large red oval) binding to its target site (red square), co-associated factors (small red ovals) mediate control of translation through interaction with 5' initiation factors, elongation factors, ribosomal constituents or 3' end processing factors as part of a higher order mRNP complex. In response to intrinsic or extrinsic cellular cues (Black arrow), remodeling of the mRNP occurs (e.g., recruitment of additional factors (yellow oval), expulsion of existing components (red oval), modification of existing component (blue oval)), resulting in altered control of translation. Hexagon, polyadenylation signal; (B) Control of mRNA translation often involves multiple distinct RBPs (R1 and R2, large red and red oval, respectively) interacting with the same target mRNA. When the RBPs exert similar function in any given cellular context, their activities lead to additive or synergistic regulation of translational output; (C) When the bound RBPs exert opposing functions, mRNA translational output reflects integration of conflicting RBP inputs. A combinatorial assembly of effector co-factors would permit recruitment, expulsion and/or modification of the higher order mRNP complex in response to changing cellular cues, resulting in mRNA-specific translational output. In this example the activity of a repressor RBP (R1, large red oval) and associated co-factors (small red ovals) overrides the activator function of a neighboring RBP (R2, large green oval) and its associated co-factors (small green ovals). However, modulation of R1 and/or R2 directly, modulation of co-factor function and/or association attenuates the ability of R1 to inhibit R2 activator activity. Interaction of the distinct RBPs (R1 and R2) thus results in mRNA- and cell context-dependent combinatorial assembly of recruited co-factors specific to the RBP occupancy.
	Figure 3. Musashi co-association with other RBPs is RNA-independent (A) Forty oocytes were co-injected with mRNA encoding GFP-Musashi1 (Msi) and either GST-BRaf, GST-Msi, GST-CPEB1 or GST-CPEB4. The GFP tagged mammalian Musashi1 protein construct [75], and GST-tagged human CPEB1 [91] have been described previously. The CPEB4 protein construct was generated by a PCR mediated subclone of KIAA 1673 (Origene Technologies, Inc., Rockville, MD USA) into the pXen2 vector [92]. In vitro transcribed RNA was prepared for each construct and injected into immature oocytes. The injected oocytes were incubated overnight to express the introduced proteins then lysed. Lysates were then subjected to GST-pulldown and treatment with RNase1 as described [75]. Associations were visualized by western blotting. GST-XMsi1, GST-CPEB1 and GST-CPEB4 associate with GFP-Msi in an RNase1 independent manner, while the GST-BRaf does not (upper panel, arrowhead); (B) Oocytes were injected with the indicated mRNA combinations and CPEB1 (left panel) or CPEB4 (right panel) oligomerization assessed by GFP western blotting (arrowhead, upper panels) in the presence or absence of added Rnase1, essentially as described in panel (a) above. No co-association was seen with BRaf. The expressed CPEB4 protein runs as a doublet in these experiments; (C) Oocytes were injected with the indicated mRNA combinations and CPEB1:CPEB4 co-association assessed by GFP western blotting, as described in panels (A,B).

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