The ERK-RSK1 activation by growth factors at G2 phase delays cell cycle progression and reduces mitotic aberrations.
Growth factors accelerate G0 to S progression in the cell cycle, however, the roles of growth factors in other cell cycle phases are largely unknown. Here, we show that treatment of HeLa cells with hepatocyte growth factor (HGF) at G2 phase induced the G2/M transition delay as evidenced by FACS analysis as well as by mitotic index and time-lapse analyses. Growth factors such as epidermal growth factor (EGF) and fibroblast growth factor (FGF) also induced G2/M transition delay like HGF. HGF treatment at G2 phase causes a delayed activation of cyclin B1-associated kinase and a diminished nuclear translocation of cyclin B1. Either U0126, a MAPK kinase (MEK) inhibitor, or kinase-dead mutant of ribosomal S6 kinase (RSK) abolished the delay. Additionally, knockdown of RSK1, but not RSK2, with siRNA abrogated the delay, indicating that the extracellular-regulated protein kinase (ERK)-RSK1 mediates the HGF-induced delay. We further found that the delay in G2/M transition of cells expressing oncogenic HGF receptor, M1268T, was abolished by RSK1 knockdown. Intriguingly, we observed that HGF induced chromosomal segregation defects, and depletion of RSK1, but not RSK2, aggravated these chromosomal aberrations. Taken together, the ERK-RSK1 activation by growth factors delays G2/M transition and this might be required to maintain genomic integrity during growth factor stimulation.
Nam
Hyun-Ja
HJ
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, South Korea.
Kim
Sujeong
S
Lee
Min-Woo
MW
Lee
Bok-Soon
BS
Hara
Toshihiro
T
Saya
Hideyuki
H
Cho
Hyeseong
H
Lee
Jae-Ho
JH
D064007:Ataxia Telangiectasia Mutated Proteins; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D020090:Chromosome Segregation / Q000187:drug effects; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016195:G2 Phase / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects*; D050505:Mutant Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C534699:CCNB1 protein, human; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D025521:Tumor Suppressor Proteins; D019859:Proto-Oncogene Proteins c-met; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D016203:CDC2 Protein Kinase; D048049:Extracellular Signal-Regulated MAP Kinases