title: Inactivation of MyoD-mediated expression of p21 in tumor cell lines.
abstract: The basic helix-loop-helix protein MyoD induces muscle structural gene expression and cell cycle withdrawal in many nontransformed cell lines. We show that MyoD activation of transcription of the cyclin-dependent kinase inhibitor p21 does not require synthesis of an intermediary protein. In most of the rhabdomyosarcoma and other solid tumor cell lines that we analyzed, p21 levels were abnormally low and correlated with the combined inactivity of MyoD and p53, two known transcriptional activators of p21. Loss of MyoD activation of p21 transcription correlated with the failure to arrest in G1, and expression of p21 caused accumulation of cells in G1, further supporting a role for p21 in MyoD-induced cell cycle arrest. Finally, different tumor types have inactivated distinct factors necessary for p21 expression, because p21 expression was reconstituted in hybrid cell lines. We propose that p21 integrates growth-inhibitory signals from independent p53 and basic helix-loop-helix pathways, and that in the majority of tumor cell lines, both pathways are abrogated.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Otten
authors.forename: E J
authors.initials: EJ
authors.lastname: Firpo
authors.forename: A N
authors.initials: AN
authors.lastname: Gerber
authors.forename: L L
authors.initials: LL
authors.lastname: Brody
authors.forename: J M
authors.initials: JM
authors.lastname: Roberts
authors.forename: S J
authors.initials: SJ
authors.lastname: Tapscott
mesh_terms: D000818:Animals; D002453:Cell Cycle; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000378:metabolism*; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D017570:MyoD Protein / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D017570:MyoD Protein; D016159:Tumor Suppressor Protein p53