title: Retinoblastoma protein and MyoD function together to effect the repression of Fra-1 and in turn cyclin D1 during terminal cell cycle arrest associated with myogenesis.
abstract: The acquisition of skeletal muscle-specific function and terminal cell cycle arrest represent two important features of the myogenic differentiation program. These cellular processes are distinct and can be separated genetically. The lineage-specific transcription factor MyoD and the retinoblastoma protein pRb participate in both of these cellular events. Whether and how MyoD and pRb work together to effect terminal cell cycle arrest is uncertain. To address this question, we focused on cyclin D1, whose stable repression is required for terminal cell cycle arrest and execution of myogenesis. MyoD and pRb are both required for the repression of cyclin D1; their actions, however, were found not to be direct. Rather, they operate to regulate the immediate early gene Fra-1, a critical player in mitogen-dependent induction of cyclin D1. Two conserved MyoD-binding sites were identified in an intronic enhancer of Fra-1 and shown to be required for the stable repression of Fra-1 and, in turn, cyclin D1. Localization of MyoD alone to the intronic enhancer of Fra-1 in the absence of pRb was not sufficient to elicit a block to Fra-1 induction; pRb was also recruited to the intronic enhancer in a MyoD-dependent manner. These observations suggest that MyoD and pRb work together cooperatively at the level of the intronic enhancer of Fra-1 during terminal cell cycle arrest. This work reveals a previously unappreciated link between a lineage-specific transcription factor, a tumor suppressor, and a proto-oncogene in the control of an important facet of myogenic differentiation.
authors.affiliation: From the Dana-Farber Cancer Institute, Boston, Massachusetts 02215.
authors.forename: Hasan N
authors.initials: HN
authors.lastname: Rajabi
authors.affiliation: From the Dana-Farber Cancer Institute, Boston, Massachusetts 02215, the Cancer Research Institute of Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan, and.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Takahashi
authors.affiliation: From the Dana-Farber Cancer Institute, Boston, Massachusetts 02215, the Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111 mewen@tuftsmedicalcenter.org.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Ewen
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002453:Cell Cycle; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D019938:Cyclin D1 / Q000378:metabolism*; D004247:DNA; D017931:DNA Primers; D051379:Mice; D008969:Molecular Sequence Data; D024510:Muscle Development; D017570:MyoD Protein / Q000502:physiology*; D016133:Polymerase Chain Reaction; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000502:physiology*; D000099169:Fos-Related Antigen 1
chemical_list: D019938:Cyclin D1; D004247:DNA; D017931:DNA Primers; D017570:MyoD Protein; D016760:Proto-Oncogene Proteins c-fos; D012319:RNA Polymerase II; D016160:Retinoblastoma Protein; D000099169:Fos-Related Antigen 1
keywords: Cell Differentiation; Fra-1; Gene Regulation; MyoD; Myogenesis; Terminal Cell Cycle Arrest; Transcription Enhancer; Transcription Factor; pRb