MyoD prevents cyclinA/cdk2 containing E2F complexes formation in terminally differentiated myocytes (original) (raw)

Oncogene volume 14, pages 1171–1184 (1997)Cite this article

Abstract

Withdrawal from the cell cycle of differentiating myocytes is regulated by the myogenic basic helix – loop – helix (bHLH) protein MyoD and the pocket proteins pRb, p107 and pRb2/p130. Downstream effectors of `pocket' proteins are the components of the E2F family of transcription factors, which regulate the G1/S-phase transition. We analysed by EMSA the composition of E2F complexes in cycling, quiescent undifferentiated and differentiated C2C12 skeletal muscle cells. An E2F complex containing mainly E2F4 and pRb2/p130 (E2F-G0/G1 complex) appears when DNA synthesis arrests, replacing the cyclinA/cdk2 containing E2F complex of proliferating myoblasts (E2F-G1/S complex). Serum stimulation reinduces DNA synthesis and the re-appearance of E2F-G1/S complexes in quiescent myoblasts but not in differentiated C2C12 myotubes. In differentiating C2C12 cells, E2F complexes switch and DNA synthesis in response to serum are prevented when MyoD DNA binding activity and the cdks inhibitor MyoD downstream effector p21 are induced. Thus, during myogenic differentiation, formation of E2F4 and pRb2/p130 containing complexes is an early event, but not enough on its own to prevent the re-activation of DNA synthesis. Using a subclone of C3H10T1/2 mouse fibroblasts stably expressing Estrogen Receptor-MyoD (ER-MyoD) chimerae, we found that estrogen directed MyoD activation prevents the re-association of cyclinA/cdk2 to the E2F4 containing complex following serum stimulation and this correlates with suppression of E2F activity and the inability of cells to re-enter the cell cycle. Our data indicate that, in differentiating myocytes, one mechanism through which MyoD induces permanent cell cycle arrest involves p21 upregulation and suppression of the proliferation-associated cdks-containing E2F complexes formation.

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Authors and Affiliations

  1. Fondazione A Cesalpino and I Clinica Medica, University of Rome 'La Sapienza', Viale del Policlinico 155, Roma, 00161, Italy
    Pier Lorenzo Puri, Vito Lelio Burgio, Paolo Chirillo, Gioacchino Natoli & Massimo Levrero
  2. Dipartimento di Medicina Interna, University of L'Aquila, Berlin, 14195, Germany
    Clara Balsano
  3. Istituto di Tecnologie Biomediche CNR, Roma, Italy
    Letizia Ricci & Elisabetta Mattei
  4. Institute fur Molekularbiologie und Biochemie der Freien Universitat Berlin, Berlin, 14195, Germany
    Adolf Graessmann

Authors

  1. Pier Lorenzo Puri
  2. Clara Balsano
  3. Vito Lelio Burgio
  4. Paolo Chirillo
  5. Gioacchino Natoli
  6. Letizia Ricci
  7. Elisabetta Mattei
  8. Adolf Graessmann
  9. Massimo Levrero

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Puri, P., Balsano, C., Burgio, V. et al. MyoD prevents cyclinA/cdk2 containing E2F complexes formation in terminally differentiated myocytes.Oncogene 14, 1171–1184 (1997). https://doi.org/10.1038/sj.onc.1200941

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