TY - JOUR
T1 - G1 cyclins link proliferation, pluripotency and differentiation of embryonic stem cells
AU - Liu, Lijun
AU - Michowski, Wojciech
AU - Inuzuka, Hiroyuki
AU - Shimizu, Kouhei
AU - Nihira, Naoe Taira
AU - Chick, Joel M.
AU - Li, Na
AU - Geng, Yan
AU - Meng, Alice Y.
AU - Ordureau, Alban
AU - Kołodziejczyk, Aleksandra
AU - Ligon, Keith L.
AU - Bronson, Roderick T.
AU - Polyak, Kornelia
AU - Harper, J. Wade
AU - Gygi, Steven P.
AU - Wei, Wenyi
AU - Sicinski, Piotr
N1 - Funding Information:
We thank H.-J.Kim, M. Brown, H. Long, P. Rao, Z.Herbert,Q.Ma, J.Alberta, J. Zhou and C. D. Stiles for helpful discussions and help with experiments. This work was supported by NIH grants R01 CA202634, R01 CA132740 and P01 CA080111 (to P.S.) and AG011085 (to J.W.H.). A.O. was supported by an Edward R. and Anne G. Lefler Center Postdoctoral Fellowship.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - Progression of mammalian cells through the G1 and S phases of the cell cycle is driven by the D-type and E-type cyclins. According to the current models, at least one of these cyclin families must be present to allow cell proliferation. Here, we show that several cell types can proliferate in the absence of all G1 cyclins. However, following ablation of G1 cyclins, embryonic stem (ES) cells attenuated their pluripotent characteristics, with the majority of cells acquiring the trophectodermal cell fate. We established that G1 cyclins, together with their associated cyclin-dependent kinases (CDKs), phosphorylate and stabilize the core pluripotency factors Nanog, Sox2 and Oct4. Treatment of murine ES cells, patient-derived glioblastoma tumour-initiating cells, or triple-negative breast cancer cells with a CDK inhibitor strongly decreased Sox2 and Oct4 levels. Our findings suggest that CDK inhibition might represent an attractive therapeutic strategy by targeting glioblastoma tumour-initiating cells, which depend on Sox2 to maintain their tumorigenic potential.
AB - Progression of mammalian cells through the G1 and S phases of the cell cycle is driven by the D-type and E-type cyclins. According to the current models, at least one of these cyclin families must be present to allow cell proliferation. Here, we show that several cell types can proliferate in the absence of all G1 cyclins. However, following ablation of G1 cyclins, embryonic stem (ES) cells attenuated their pluripotent characteristics, with the majority of cells acquiring the trophectodermal cell fate. We established that G1 cyclins, together with their associated cyclin-dependent kinases (CDKs), phosphorylate and stabilize the core pluripotency factors Nanog, Sox2 and Oct4. Treatment of murine ES cells, patient-derived glioblastoma tumour-initiating cells, or triple-negative breast cancer cells with a CDK inhibitor strongly decreased Sox2 and Oct4 levels. Our findings suggest that CDK inhibition might represent an attractive therapeutic strategy by targeting glioblastoma tumour-initiating cells, which depend on Sox2 to maintain their tumorigenic potential.
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U2 - 10.1038/ncb3474
DO - 10.1038/ncb3474
M3 - Article
C2 - 28192421
AN - SCOPUS:85012254451
VL - 19
SP - 177
EP - 188
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 3
ER -
