title: Hyper-mitogenic drive coexists with mitotic incompetence in senescent cells.
abstract: When the cell cycle is arrested, even though growth-promoting pathways such as mTOR are still active, then cells senesce. For example, induction of either p21 or p16 arrests the cell cycle without inhibiting mTOR, which, in turn, converts p21/p16-induced arrest into senescence (geroconversion). Here we show that geroconversion is accompanied by dramatic accumulation of cyclin D1 followed by cyclin E and replicative stress. When p21 was switched off, senescent cells (despite their loss of proliferative potential) progressed through S phase, and levels of cyclins D1 and E dropped. Most cells entered mitosis and then died, either during mitotic arrest or after mitotic slippage, or underwent endoreduplication. Next, we investigated whether inhibition of mTOR would prevent accumulation of cyclins and loss of mitotic competence in p21-arrested cells. Both nutlin-3, which inhibits mTOR in these cells, and rapamycin suppressed geroconversion during p21-induced arrest, decelerated accumulation of cyclins D1 and E and decreased replicative stress. When p21 was switched off, cells successfully progressed through both S phase and mitosis. Also, senescent mouse embryonic fibroblasts (MEFs) overexpressed cyclin D1. After release from cell cycle arrest, senescent MEFs entered S phase but could not undergo mitosis and did not proliferate. We conclude that cellular senescence is characterized by futile hyper-mitogenic drive associated with mTOR-dependent mitotic incompetence.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Leontieva
authors.forename: Felicia
authors.initials: F
authors.lastname: Lenzo
authors.forename: Zoya N
authors.initials: ZN
authors.lastname: Demidenko
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Blagosklonny
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008938:Mitosis / Q000235:genetics / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D007093:Imidazoles; D010879:Piperazines; D019938:Cyclin D1; C482205:nutlin 3; D058570:TOR Serine-Threonine Kinases