Cell
Volume 72, Issue 3, 12 February 1993, Pages 309-324
Journal home page for Cell

Article
Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation

https://doi.org/10.1016/0092-8674(93)90110-CGet rights and content

Abstract

The experiments reported here document that the tumor suppressor retinoblastoma protein (pRB) plays an important role in the production and maintenance of the terminally differentiated phenotype of muscle cells. We show that pRB inactivation, through either phosphorylation, binding to T antigen, or genetic alteration, inhibits myogenesis. Moreover, inactivation of pRB in terminally differentiated cells allows them to reenter the cell cycle. In addition to its involvement in the myogenic activities of MyoD, pRB is also required for the cell growth-inhibitory activity of this myogenic factor. We also show that pRB and MyoD directly bind to each other, both in vivo and in vitro, through a region that involves the pocket and the basic-helix-loop-helix domains, respectively. All the results obtained are consistent with the proposal that the effects of MyoD on the cell cycle and of pRB on the myogenic pathway result from the direct binding of the two molecules.

References (98)

  • J.A. DeCaprio et al.

    SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene

    Cell

    (1988)
  • J.A. DeCaprio et al.

    The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element

    Cell

    (1989)
  • A. Giordano et al.

    A 60 kd cdc2-associated polypeptide complexes with the E1A proteins in adenovirus-infected cells

    Cell

    (1989)
  • D.W. Goodrich et al.

    The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle

    Cell

    (1991)
  • A. Graessmann et al.

    The relationship of polyoma virus-induced tumor (T) antigen to activation of DNA synthesis in rat myotubes

    Dev. Biol.

    (1973)
  • P.W. Hinds et al.

    Regulation of retinoblastoma protein functions by ectopic expression of human cyclins

    Cell

    (1992)
  • W.G. Kaelin et al.

    Identification of cellular proteins that can interact specifically with the TE1A-binding region of the retinoblastoma gene product

    Cell

    (1991)
  • D. Kalderon et al.

    In vitro mutagenesis of a putative DNA-binding domain of SV40 large T

    Virology

    (1984)
  • S.A. LaRocca et al.

    Interaction with normal cells suppresses the transformed phenotype of v-myc-transformed quail muscle cells

    Cell

    (1989)
  • A.B. Lassar et al.

    MyoD is a sequence-specific DNA binding protein requiring a region of myc homology to bind to the muscle creatine kinase enhancer

    Cell

    (1989)
  • A.B. Lassar et al.

    Transformation by activated ras or fos prevents myogenesis by inhibiting expression of MyoD1

    Cell

    (1989)
  • A.B. Lassar et al.

    Functional activity of myogenic HLH proteins requires hetero-oligomerization with E12E47-like proteins in vivo

    Cell

    (1991)
  • J.W. Ludlow et al.

    SV40 large T antigen binds preferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family

    Cell

    (1989)
  • J.W. Ludlow et al.

    The retinoblastoma susceptibility gene product undergoes cell cycle-dependent dephosphorylation and binding to and release from SV40 large T

    Cell

    (1990)
  • C.J. Marshall

    Tumor suppressor genes

    Cell

    (1991)
  • S. Mittnacht et al.

    G1S phosphorylation of the retinoblastoma protein is associated with an altered affinity for the nuclear compartment

    Cell

    (1991)
  • C. Murre et al.

    A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughter-less, MyoD and myc proteins

    Cell

    (1989)
  • B. Nadal-Ginard

    Commitment, fusion, and biochemical differentiation of a myogenic cell line in the absence of DNA synthesis

    Cell

    (1978)
  • H.T. Nguyen et al.

    Reversibility of muscle differentiation in the absence of commitment: analysis of a myogenic cell line temperature-sensitive for commitment

    Cell

    (1983)
  • S. Shirodkar et al.

    The transcription factor E2F interacts with the retinoblastoma product and a p107-cyclin A complex in a cell cycle-regulated manner

    Cell

    (1992)
  • F.E. Stockdale et al.

    DNA synthesis and myogenesis

    Exp. Cell Res.

    (1961)
  • M. Wigler et al.

    Biochemical transfer of single-copy eucaryotic genes using total cellular DNA as donor

    Cell

    (1978)
  • W.E. Wright et al.

    Myogenin, a factor regulating myogenesis, has a domain homologous to MyoD

    Cell

    (1989)
  • L.R. Bandara et al.

    Cyclin A and the retinoblastoma gene product complex with a common transcription factor

    Nature

    (1991)
  • R. Bernards et al.

    Structure and expression of the murine retinoblastoma gene and characterization of its encoded protein

  • R. Bookstein et al.

    Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated RB gene

    Science

    (1990)
  • T. Braun et al.

    A novel human muscle factor related to but distinct from MyoD1 induces myogenic conversion in 10T12 fibroblasts

    EMBO J.

    (1989)
  • T. Brennan et al.

    Aberrant regulation of MyoD1 contributes to the partially defective myogenic phenotype of BC3H1 cells

    J. Cell Biol.

    (1990)
  • S. Chen et al.

    Identification of a region of simian virus 40 large T antigen required for cell transformation

    J. Virol.

    (1990)
  • J. Choi et al.

    MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle, and retinal pigmented epithelial cells into striated mononucleated myoblasts and multinucleated myotubes

  • A.R. Clarke et al.

    Requirement for a functional Rb-1 gene in murine development

    Nature

    (1992)
  • M. Crescenzi et al.

    MyoD induces growth arrest independent of differentiation in normal and transformed cells

  • D. Defeo-Jones et al.

    Cloning of cDNAs for cellular proteins that bind to the retinoblastoma gene product

    Nature

    (1991)
  • N. Dyson et al.

    The human papillomavirus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product

    Science

    (1989)
  • N. Dyson et al.

    Large T-antigens of many polyoma viruses are able to form complexes with the retinoblastoma protein

    J. Virol.

    (1990)
  • T. Endo et al.

    Transcriptional and posttranscriptional control of c-myc during myogenesis: its mRNA remains inducible in differentiated cells and does not suppress the differentiated phenotype

    Mol. Cell. Biol.

    (1986)
  • T. Endo et al.

    SV40 large T-antigen induces re-entry of terminally differentiated myotubes into the cell cycle

  • M. Fogel et al.

    Infection of muscle cultures from various species with oncogenic DNA viruses (SV40 and polyoma)

  • Y. Furukawa et al.

    Expression and state of phosphorylation of the retinoblastoma susceptibility gene product in cycling and non-cycling human hematopoietic cells

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