TY - JOUR
T1 - The ERK-RSK1 activation by growth factors at G2 phase delays cell cycle progression and reduces mitotic aberrations
AU - Nam, Hyun Ja
AU - Kim, Sujeong
AU - Lee, Min Woo
AU - Lee, Bok Soon
AU - Hara, Toshihiro
AU - Saya, Hideyuki
AU - Cho, Hyeseong
AU - Lee, Jae Ho
N1 - Funding Information:
We thank Dr. Woon-Ki Paik for his critical review of this manuscript; Dr. John Blenis (Department of Cell Biology, Harvard Medical School, Boston, MA) for HA-RSK1 kinase-dead mutant cDNA. This work was supported by Grant No. R13-2003-019 from the Korea Science & Engineering Foundation through Chronic Inflammatory Disease Research Center (to J.H.Lee).
PY - 2008/7
Y1 - 2008/7
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/43049157858
UR - https://www.scopus.com/inward/citedby.url?scp=43049157858&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2008.03.008
DO - 10.1016/j.cellsig.2008.03.008
M3 - Article
C2 - 18450423
AN - SCOPUS:43049157858
SN - 0898-6568
VL - 20
SP - 1349
EP - 1358
JO - Cellular Signalling
JF - Cellular Signalling
IS - 7
ER -