title: Rapamycin induces pluripotent genes associated with avoidance of replicative senescence.
abstract: Primary rodent cells undergo replicative senescence, independent from telomere shortening. We have recently shown that treatment with rapamycin during passages 3-7 suppressed replicative senescence in rat embryonic fibroblasts (REFs), which otherwise occurred by 10-14 passages. Here, we further investigated rapamycin-primed cells for an extended number of passages. Rapamycin-primed cells continued to proliferate without accumulation of senescent markers. Importantly, these cells retained the ability to undergo serum starvation- and etoposide-induced cell cycle arrest. The p53/p21 pathway was functional. This indicates that rapamycin did not cause either transformation or loss of cell cycle checkpoints. We found that rapamycin activated transcription of pluripotent genes, oct-4, sox-2, nanog, as well as further upregulated telomerase (tert) gene. The rapamycin-derived cells have mostly non-rearranged, near-normal karyotype. Still, when cultivated for a higher number of passages, these cells acquired a chromosomal marker within the chromosome 3. We conclude that suppression mTORC1 activity may prevent replicative senescence without transformation of rodent cells.
authors.affiliation: Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia; St.Petersburg State University; St. Petersburg, Russia.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Pospelova
authors.affiliation: Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia; St.Petersburg State University; St. Petersburg, Russia.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Bykova
authors.affiliation: Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia; St.Petersburg State University; St. Petersburg, Russia.
authors.forename: Svetlana G
authors.initials: SG
authors.lastname: Zubova
authors.affiliation: Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Katolikova
authors.affiliation: Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia.
authors.forename: Natalia M
authors.initials: NM
authors.lastname: Yartzeva
authors.affiliation: Institute of Cytology; Russian Academy of Sciences; St. Petersburg, Russia; St.Petersburg State University; St. Petersburg, Russia.
authors.forename: Valery A
authors.initials: VA
authors.lastname: Pospelov
mesh_terms: D000818:Animals; D001343:Autophagy; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D059785:Karyotype; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D019098:Telomerase; D020123:Sirolimus
keywords: aging; gerosuppression; mTOR; rapalogs; senescence