Cdk4 and Cdk6 Couple the Cell-Cycle Machinery to Cell Growth via mTORC1

  1. Romero-Pozuelo, Jesús
  2. Figlia, Gianluca
  3. Kaya, Oguzhan
  4. Martin-Villalba, Ana
  5. Teleman, Aurelio A.
Revista:
Cell Reports

ISSN: 2211-1247

Año de publicación: 2020

Volumen: 31

Número: 2

Páginas: 107504

Tipo: Artículo

DOI: 10.1016/J.CELREP.2020.03.068 GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: Cell Reports

Resumen

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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Referencias bibliográficas

  • Abe, (2013), Development, 140, pp. 237, 10.1242/dev.084111
  • Aguilar, (2010), EMBO Mol. Med., 2, pp. 338, 10.1002/emmm.201000089
  • Bockstaele, (2006), Cell Div., 1, pp. 25, 10.1186/1747-1028-1-25
  • Ciemerych, (2002), Genes Dev., 16, pp. 3277, 10.1101/gad.1023602
  • Dannenberg, (2000), Genes Dev., 14, pp. 3051, 10.1101/gad.847700
  • Datar, (2000), EMBO J., 19, pp. 4543, 10.1093/emboj/19.17.4543
  • Dolznig, (2004), Nat. Cell Biol., 6, pp. 899, 10.1038/ncb1166
  • Emmerich, (2004), Genetics, 168, pp. 867, 10.1534/genetics.104.027417
  • Fantl, (1995), Genes Dev., 9, pp. 2364, 10.1101/gad.9.19.2364
  • Finn, (2009), Breast Cancer Res., 11, pp. R77, 10.1186/bcr2419
  • Finn, (2016), Breast Cancer Res., 18, pp. 17, 10.1186/s13058-015-0661-5
  • Franco, (2016), Cell Rep., 14, pp. 979, 10.1016/j.celrep.2015.12.094
  • Georgia, (2004), J. Clin. Invest., 114, pp. 963, 10.1172/JCI22098
  • Goel, (2016), Cancer Cell, 29, pp. 255, 10.1016/j.ccell.2016.02.006
  • Groenewoud, (2013), Biochem. Soc. Trans., 41, pp. 951, 10.1042/BST20130037
  • Henske, (2016), Nat. Rev. Dis. Primers, 2, pp. 16035, 10.1038/nrdp.2016.35
  • Herrera, (1996), Mol. Cell. Biol., 16, pp. 2402, 10.1128/MCB.16.5.2402
  • Herrera-Abreu, (2016), Cancer Res., 76, pp. 2301, 10.1158/0008-5472.CAN-15-0728
  • Jewell, (2015), Science, 347, pp. 194, 10.1126/science.1259472
  • Kato, (1993), Genes Dev., 7, pp. 331, 10.1101/gad.7.3.331
  • Kim, (2019), Nat. Cell Biol., 21, pp. 63, 10.1038/s41556-018-0205-1
  • Kim, (2013), Mol. Cell, 49, pp. 172, 10.1016/j.molcel.2012.10.003
  • Kitagawa, (1996), EMBO J., 15, pp. 7060, 10.1002/j.1460-2075.1996.tb01097.x
  • Knudsen, (2017), Trends Cancer, 3, pp. 39, 10.1016/j.trecan.2016.11.006
  • Kozar, (2004), Cell, 118, pp. 477, 10.1016/j.cell.2004.07.025
  • Kwiatkowski, (2002), Hum. Mol. Genet., 11, pp. 525, 10.1093/hmg/11.5.525
  • Lee, (2014), Nature, 510, pp. 547, 10.1038/nature13267
  • Lim, (2013), Development, 140, pp. 3079, 10.1242/dev.091744
  • Lopez-Mejia, (2017), Mol. Cell, 68, pp. 336, 10.1016/j.molcel.2017.09.034
  • Madeira, (2019), Nucleic Acids Res., 47, pp. W636, 10.1093/nar/gkz268
  • Martínez-Carreres, (2019), Cancer Res., 79, pp. 5245, 10.1158/0008-5472.CAN-19-0708
  • Meyer, (2000), EMBO J., 19, pp. 4533, 10.1093/emboj/19.17.4533
  • Michaloglou, (2018), Mol. Cancer Ther., 17, pp. 908, 10.1158/1535-7163.MCT-17-0537
  • Mossmann, (2018), Nat. Rev. Cancer, 18, pp. 744, 10.1038/s41568-018-0074-8
  • Neufeld, (1998), Cell, 93, pp. 1183, 10.1016/S0092-8674(00)81462-2
  • Nicastro, (2017), Biomolecules, 7, pp. E48, 10.3390/biom7030048
  • Nur Husna, (2018), Ther. Adv. Med. Oncol., 10, 10.1177/1758835918808509
  • Rane, (1999), Nat. Genet., 22, pp. 44, 10.1038/8751
  • Romero-Pozuelo, (2017), Dev. Cell, 42, pp. 376, 10.1016/j.devcel.2017.07.019
  • Rupes, (2002), Trends Genet., 18, pp. 479, 10.1016/S0168-9525(02)02745-2
  • Sage, (2000), Genes Dev., 14, pp. 3037, 10.1101/gad.843200
  • Satyanarayana, (2009), Oncogene, 28, pp. 2925, 10.1038/onc.2009.170
  • Varsano, (2017), Cell Rep., 20, pp. 397, 10.1016/j.celrep.2017.06.057
  • Vermeulen, (2003), Cell Prolif., 36, pp. 131, 10.1046/j.1365-2184.2003.00266.x
  • Wang, (2006), Proc. Natl. Acad. Sci. USA, 103, pp. 11567, 10.1073/pnas.0603363103
  • Winkelmann, (1987), Klin. Wochenschr., 65, pp. 1115, 10.1007/BF01734832
  • Xue, (2019), Nat. Commun., 10, pp. 558, 10.1038/s41467-018-06958-9
  • Zacharek, (2005), Cancer Res., 65, pp. 11354, 10.1158/0008-5472.CAN-05-2236
  • Zhang, (2003), J. Clin. Invest., 112, pp. 1223, 10.1172/JCI200317222