Cdk4 and Cdk6 couple the cell-cycle machinery to cell growth via mTORC1
Cell growth is coupled to cell-cycle progression in mitotically proliferating mammalian cells, but the underlying molecular mechanisms are not well understood. CyclinD-Cdk4/6 is known to phosphorylate RB to promote S-phase entry, but recent work suggests they have additional functions. We show here...
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| Hauptverfasser: | , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
April 14, 2020
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| In: |
Cell reports
Year: 2020, Jahrgang: 31, Heft: 2 |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2020.03.068 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.celrep.2020.03.068
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| Verfasserangaben: | Jesus Romero-Pozuelo, Gianluca Figlia, Oguzhan Kaya, Ana Martin-Villalba, and Aurelio A. Teleman |
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| 520 | |a Cell growth is coupled to cell-cycle progression in mitotically proliferating mammalian cells, but the underlying molecular mechanisms are not well understood. CyclinD-Cdk4/6 is known to phosphorylate RB to promote S-phase entry, but recent work suggests they have additional functions. We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452. Pharmacological inhibition of Cdk4/6 leads to a rapid, TSC2-dependent reduction of mTORC1 activity in multiple human and mouse cell lines, including breast cancer cells. By simultaneously driving mTORC1 and E2F, CyclinD-Cdk4/6 couples cell growth to cell-cycle progression. Consistent with this, we see that mTORC1 activity is cell cycle dependent in proliferating neural stem cells of the adult rodent brain. We find that Cdk4/6 inhibition reduces cell proliferation partly via TSC2 and mTORC1. This is of clinical relevance, because Cdk4/6 inhibitors are used for breast cancer therapy. | ||
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