title: Newt myotubes reenter the cell cycle by phosphorylation of the retinoblastoma protein.
abstract: Withdrawal from the cell cycle is an essential aspect of vertebrate muscle differentiation and requires the retinoblastoma (Rb) protein that inhibits expression of genes needed for cell cycle entry. It was shown recently that cultured myotubes derived from the Rb-/- mouse reenter the cell cycle after serum stimulation (Schneider, J.W., W. Gu, L. Zhu, V. Mahdavi, and B. Nadal-Ginard. 1994. Science (Wash. DC). 264:1467-1471). In contrast with other vertebrates, adult urodele amphibians such as the newt can regenerate their limbs, a process involving cell cycle reentry and local reversal of differentiation. Here we show that myotubes formed in culture from newt limb cells are refractory to several growth factors, but they undergo S phase after serum stimulation and accumulate 4N nuclei. This response to serum is inhibited by contact with mononucleate cells. Despite the phenotypic parallel with Rb-/- mouse myotubes, Rb is expressed in the newt myotubes, and its phosphorylation via cyclin-dependent kinase 4/6 is required for cell cycle reentry. Thus, the postmitotic arrest of urodele myotubes, although intact in certain respects, can be undermined by a pathway that is inactive in other vertebrates. This may be important for the regenerative ability of these animals.
authors.affiliation: Ludwig Institute for Cancer Research, University College London, United Kingdom.
authors.forename: E M
authors.initials: EM
authors.lastname: Tanaka
authors.forename: A A
authors.initials: AA
authors.lastname: Gann
authors.forename: P B
authors.initials: PB
authors.lastname: Gates
authors.forename: J P
authors.initials: JP
authors.lastname: Brockes
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001769:Blood; D002352:Carrier Proteins / Q000502:physiology; D002452:Cell Count; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D004261:DNA Replication; D004791:Enzyme Inhibitors; D006133:Growth Substances / Q000494:pharmacology; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects / Q000502:physiology*; D012455:Salamandridae
chemical_list: D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D006133:Growth Substances; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D017346:Protein Serine-Threonine Kinases; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases