Proline Isomerase Pin1 Represses Terminal Differentiation and Myocyte Enhancer Factor 2C Function in Skeletal Muscle Cells

Cadherins are a gene family encoding calcium-dependent cell adhesion proteins which are thought to act in the establishment and maintenance of tissue organization. M-cadherin, one member of the family, has been found in myogenic cells of somitic origin during embryogenesis and in the adult. These findings have suggested that M-cadherin is involved in the regulation of morphogenesis of skeletal muscle cells. Therefore, we investigated the function of M-cadherin in the fusion of myoblasts into myotubes (terminal differentiation) in cell culture. Furthermore, we tested whether M-cadherin might influence (a) the expression of troponin T, a typical marker of biochemical differentiation of skeletal muscle cells, and (b) withdrawal of myoblasts from the cell cycle (called terminal commitment). The studies were performed by using antagonistic peptides which correspond to sequences of the putative M-cadherin binding domain. Analogous peptides of N-cadherin have previously been shown to interfere functionally with the N-cadherin-mediated cell adhesion. In the presence of antagonistic M-cadherin peptides, the fusion of myoblasts into myotubes was inhibited. Analysis of troponin T revealed that it was downregulated at the protein level although its mRNA was still detectable. In addition, withdrawal from the cell cycle typical for terminal commitment of muscle cells was not complete in fusion-blocked myogenic cells. Finally, expression of M-cadherin antisense RNA reducing the expression of the endogenous M-cadherin protein interfered with the fusion process of myoblasts. Our data imply that M-cadherin-mediated myoblast interaction plays an important role in terminal differentiation of skeletal muscle cells.

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Oncogenic Ras-Induced Proliferation Requires Autocrine Fibroblast Growth Factor 2 Signaling in Skeletal Muscle Cells

The Journal of Cell Biology ◽

10.1083/jcb.152.6.1301 ◽

2001 ◽

Vol 152 (6) ◽

pp. 1301-1306 ◽

Cited By ~ 23

Author(s):

Yuri V. Fedorov ◽

R. Scott Rosenthal ◽

Bradley B. Olwin

Keyword(s):

Skeletal Muscle ◽

Ectopic Expression ◽

Terminal Differentiation ◽

Biological Response ◽

Muscle Cells ◽

Sodium Chlorate ◽

Skeletal Muscle Cells ◽

Specific Gene ◽

Fibroblast Growth ◽

Oncogenic Ras

Constitutively activated Ras proteins are associated with a large number of human cancers, including those originating from skeletal muscle tissue. In this study, we show that ectopic expression of oncogenic Ras stimulates proliferation of the MM14 skeletal muscle satellite cell line in the absence of exogenously added fibroblast growth factors (FGFs). MM14 cells express FGF-1, -2, -6, and -7 and produce FGF protein, yet they are dependent on exogenously supplied FGFs to both maintain proliferation and repress terminal differentiation. Thus, the FGFs produced by these cells are either inaccessible or inactive, since the endogenous FGFs elicit no detectable biological response. Oncogenic Ras-induced proliferation is abolished by addition of an anti–FGF-2 blocking antibody, suramin, or treatment with either sodium chlorate or heparitinase, demonstrating an autocrine requirement for FGF-2. Oncogenic Ras does not appear to alter cellular export rates of FGF-2, which does not possess an NH2-terminal or internal signal peptide. However, oncogenic Ras does appear to be involved in releasing or activating inactive, extracellularly sequestered FGF-2. Surprisingly, inhibiting the autocrine FGF-2 required for proliferation has no effect on oncogenic Ras-mediated repression of muscle-specific gene expression. We conclude that oncogenic Ras-induced proliferation of skeletal muscle cells is mediated via a unique and novel mechanism that is distinct from Ras-induced repression of terminal differentiation and involves activation of extracellularly localized, inactive FGF-2.

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SV40 large T antigen-induced inhibition of terminal differentiation of primary skeletal muscle cells is associated with a block in the expression of MyoD and myogenin

Molecular Biology Reports ◽

10.1007/bf00990546 ◽

1994 ◽

Vol 20 (3) ◽

pp. 143-148 ◽

Cited By ~ 1

Author(s):

F. A. J. M. Van De Klundert ◽

H. Bloemendal

Keyword(s):

Skeletal Muscle ◽

Terminal Differentiation ◽

Muscle Cells ◽

T Antigen ◽

Skeletal Muscle Cells ◽

Large T Antigen ◽

Sv40 Large T Antigen

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tk Enzyme expression in differentiating muscle cells is regulated through an internal segment of the cellular tk gene.

Molecular and Cellular Biology ◽

10.1128/mcb.4.9.1777 ◽

1984 ◽

Vol 4 (9) ◽

pp. 1777-1784 ◽

Cited By ~ 35

Author(s):

G F Merrill ◽

S D Hauschka ◽

S L McKnight

Keyword(s):

Skeletal Muscle ◽

Enzyme Activity ◽

Thymidine Kinase ◽

Terminal Differentiation ◽

Muscle Cells ◽

Muscle Differentiation ◽

Skeletal Muscle Cells ◽

Deficient Mouse ◽

Enzyme Expression

Thymidine kinase (tk) enzyme expression is shut down when cultured skeletal muscle cells terminally differentiate. This regulation is mediated by a rapid and specific decline in the abundance of cellular tk mRNA. tk-deficient mouse myoblasts were transformed to the tk-positive phenotype by using both the cellular tk gene of the chicken and the herpesvirus tk gene. Myoblasts transformed with the cellular tk gene effectively regulate tk enzyme activity upon terminal differentiation. Conversely, myoblasts transformed with the herpesvirus tk gene continue to express tk enzyme activity in postreplicative muscle cells. A regulated pattern of expression is retained when the promoter of the cellular tk gene is replaced by the promoter of the herpesvirus tk gene. Moreover, the cellular tk gene is appropriately regulated during terminal muscle differentiation when its 3' terminus is removed and replaced by the terminus of the viral tk gene. Thus, the element of the cellular tk gene sufficient to specify its regulation is entirely intragenic.

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tk Enzyme expression in differentiating muscle cells is regulated through an internal segment of the cellular tk gene

Molecular and Cellular Biology ◽

10.1128/mcb.4.9.1777-1784.1984 ◽

1984 ◽

Vol 4 (9) ◽

pp. 1777-1784

Author(s):

G F Merrill ◽

S D Hauschka ◽

S L McKnight

Keyword(s):

Skeletal Muscle ◽

Enzyme Activity ◽

Thymidine Kinase ◽

Terminal Differentiation ◽

Muscle Cells ◽

Muscle Differentiation ◽

Skeletal Muscle Cells ◽

Deficient Mouse ◽

Enzyme Expression

Thymidine kinase (tk) enzyme expression is shut down when cultured skeletal muscle cells terminally differentiate. This regulation is mediated by a rapid and specific decline in the abundance of cellular tk mRNA. tk-deficient mouse myoblasts were transformed to the tk-positive phenotype by using both the cellular tk gene of the chicken and the herpesvirus tk gene. Myoblasts transformed with the cellular tk gene effectively regulate tk enzyme activity upon terminal differentiation. Conversely, myoblasts transformed with the herpesvirus tk gene continue to express tk enzyme activity in postreplicative muscle cells. A regulated pattern of expression is retained when the promoter of the cellular tk gene is replaced by the promoter of the herpesvirus tk gene. Moreover, the cellular tk gene is appropriately regulated during terminal muscle differentiation when its 3' terminus is removed and replaced by the terminus of the viral tk gene. Thus, the element of the cellular tk gene sufficient to specify its regulation is entirely intragenic.

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