title: Arrest of mammalian fibroblasts in G1 in response to actin inhibition is dependent on retinoblastoma pocket proteins but not on p53.
abstract: p53 and the retinoblastoma (RB) pocket proteins are central to the control of progression through the G1 phase of the cell cycle. The RB pocket protein family is downstream of p53 and controls S-phase entry. Disruption of actin assembly arrests nontransformed mammalian fibroblasts in G1. We show that this arrest requires intact RB pocket protein function, but surprisingly does not require p53. Thus, mammalian fibroblasts with normal pocket protein function reversibly arrest in G1 on exposure to actin inhibitors regardless of their p53 status. By contrast, pocket protein triple knockout mouse embryo fibroblasts and T antigen-transformed rat embryo fibroblasts lacking both p53 and RB pocket protein function do not arrest in G1. Fibroblasts are very sensitive to actin inhibition in G1 and arrest at drug concentrations that do not affect cell adhesion or cell cleavage. Interestingly, G1 arrest is accompanied by inhibition of surface ruffling and by induction of NF2/merlin. The combination of failure of G1 control and of tetraploid checkpoint control can cause RB pocket protein-suppressed cells to rapidly become aneuploid and die after exposure to actin inhibitors, whereas pocket protein-competent cells are spared. Our results thus establish that RB pocket proteins can be uniquely targeted for tumor chemotherapy.
authors.affiliation: Institut de Biologie Structurale Jean Ebel (Commissariat à l'Energie Atomique-Centre National de la Recherche Scientifique-Université Joseph Fourier), Grenoble cedex 1, France.
authors.forename: Olivier D
authors.initials: OD
authors.lastname: Lohez
authors.forename: Caroline
authors.initials: C
authors.lastname: Reynaud
authors.forename: Franck
authors.initials: F
authors.lastname: Borel
authors.forename: Paul R
authors.initials: PR
authors.lastname: Andreassen
authors.forename: Robert L
authors.initials: RL
authors.lastname: Margolis
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects / Q000235:genetics; D003571:Cytochalasin B / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005333:Fetus; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D025581:Neurofibromin 2 / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics
chemical_list: D000199:Actins; D000952:Antigens, Polyomavirus Transforming; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018797:Cell Cycle Proteins; D025581:Neurofibromin 2; D011500:Protein Synthesis Inhibitors; D016160:Retinoblastoma Protein; D013844:Thiazoles; D053778:Thiazolidines; D016159:Tumor Suppressor Protein p53; C024794:dihydrocytochalasin B; D003571:Cytochalasin B; C037067:latrunculin A