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Deletion of the p107/p130-binding domain of Mip130/LIN-9 bypasses the requirement for CDK4 activity for the dissociation of Mip130/LIN-9 from p107/p130-E2F4 complex.

ABSTRACT: Mip130/LIN-9 is part of a large complex that includes homologs of the Drosophila dREAM (drosophila RB-like, E2F, and Myb) and C. elegans DRM complexes. This complex also includes proteins such as Mip40/LIN-37, Mip120/LIN-54, and LIN-52. In mammalian cells, Mip130/LIN-9 specifically associates with the p107/p130-E2F4 repressor complex in G0/G1 and with B-Myb in S-phase. However, little is known about how the transition occurs and whether Mip130/LIN-9 contributes to the repressor effect of p107/p130. In this report, we demonstrate that Mip130/LIN-9, Mip40/LIN-37, Mip120/LIN-54, and Sin3b form a core complex, the Mip Core Complex or LIN Complex (MCC/LINC), which is detectable in all phases of the cell cycle. This complex specifically recruits transcriptional repressors such as p107, p130, E2F4 and HDAC1 in G0/G1, and B-Myb in S-phase. Importantly, we provide strong evidence that the transition between repressors and activators of transcription is mediated by CDK4, through the phosphorylation of the pocket proteins, p107 and p130. The requirement for CDK4 activity is bypassed by the deletion of the first 84 amino acids (Mip130/LIN-9(Delta84)), since this mutant is unable to interact with p107/p130 in G0/G1, while maintaining its association with B-Myb. Importantly, the Mip130/LIN-9(Delta84) allele rescues the low expression of G1/S genes observed in CDK4(-/-) MEFs demonstrating that Mip130/LIN-9 contributes to the repression of these E2F-regulated genes in G0/G1.

SUBMITTER: Sandoval R

PROVIDER: S-EPMC2757496 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLow differentiation rates of mesenchymal stem cells (MSCs) limit their therapeutic effects on patients in clinical studies. Our previous study demonstrated that overexpressing p130 or E2F4 affected the multipotential differentiation of MSCs, and the underlying mechanism was attributed to the regulation of the G1 phase. Improving the efficiency of MSC differentiation into epithelial cells is considered to be a new method. Therefore, this study was conducted to evaluate the effects of overexpressing p130 or E2F4 in MSCs on improving re-epithelization in lipopolysaccharide (LPS)-induced ARDS animals.MethodsMouse MSCs (mMSCs) stably transfected with p130 and E2F4 were transplanted intratracheally into LPS-induced ARDS mice. After 7 and 14 days, the mice were sacrificed, and the histopathology of the lungs was assessed by haematoxylin-eosin staining and lung injury scoring. Homing and differentiation of mMSCs were analysed by labelling and tracking mMSCs with NIR815 dye and immunofluorescent staining. Surfactant proteins A and C and occludin in the lungs were assessed by western blot. Permeability was evaluated by analysing the protein concentration of BALF using ELISA. Alveolar fluid clearance was assessed by absorbance measurements of BALF. Lung fibrosis was assessed by Masson's trichrome staining and Ashcroft scoring.ResultsThe engraftment of mMSCs overexpressing p130 or E2F4 led to attenuated histopathological impairment of the lung tissue, and the lung injury scores of the LPS+mBM-MSC-p130 and LPS+mBM-MSC-E2F4 groups were also decreased (p < 0.05). Overexpression of p130 or E2F4 also increased the retention of mMSCs in the lung (p < 0.05), increased differentiation into type II alveolar epithelial cells (p < 0.05), and improved alveolar epithelial permeability (p < 0.05). Additionally, mMSCs overexpressing p130 or E2F4 inhibited lung fibrosis according to the deposition of collagen and the fibrosis score in the lungs (p < 0.05).ConclusionOverexpressing p130 or E2F4 in mMSCs could further improve the injured structure and function of epithelial cells in the lungs of ARDS mice as a result of improved differentiation of mMSCs into epithelial cells.

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Deletion of the p107/p130-binding domain of Mip130/LIN-9 bypasses the requirement for CDK4 activity for the dissociation of Mip130/LIN-9 from p107/p130-E2F4 complex.

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