ABSTRACT Before replicating DNA during their reproductive cycle, our cells enter a phase called G1 during which they interpret a flood of signals that influence cell division and cell fate.

Mistakes in this process lead to cancer. An increasingly complex and coherent view of G1 signalling networks, which coordinate cell growth, proliferation, stress management and survival, is

helping to define the roots of malignancies and shows promise for the development of better cancer therapies. Access through your institution Buy or subscribe This is a preview of

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Article 10 September 2021 _CYCL_ERS’ KINASES IN CELL DIVISION: FROM MOLECULES TO CANCER THERAPY Article 29 July 2023 AN INTERMEDIATE RB–E2F ACTIVITY STATE SAFEGUARDS PROLIFERATION COMMITMENT

Article Open access 26 June 2024 REFERENCES * Morgan, D. O. Cyclin-dependent kinases: engines, clocks, and microprocessors. _Annu. Rev. Cell Dev. Biol._ 13, 261–291 (1997). Article  CAS 

PubMed  Google Scholar  * Murray, A. W. Recycling the cell cycle: cyclins revisited. _Cell_ 116, 221–234 (2004). Article  CAS  PubMed  Google Scholar  * Kelly, T. J. & Brown, G. W.

Regulation of chromosome replication. _Annu. Rev. Biochem._ 69, 829–880 (2000). Article  CAS  PubMed  Google Scholar  * Prasanth, S. G., Mendez, J., Prasanth, K. V. & Stillman, B.

Dynamics of pre-replication complex proteins during the cell division cycle. _Phil. Trans. R. Soc. Lond. B_ 359, 7–16 (2004). Article  CAS  Google Scholar  * Geng, Y. et al. Cyclin E

ablation in the mouse. _Cell_ 114, 431–443 (2003). Article  CAS  PubMed  Google Scholar  * Ortega, S. et al. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell

division in mice. _Nature Genet._ 35, 25–31 (2003). Article  CAS  PubMed  Google Scholar  * Sears, R. C. & Nevins, J. R. Signaling networks that link cell proliferation and cell fate.

_J. Biol. Chem._ 277, 11617–11620 (2002). Article  CAS  PubMed  Google Scholar  * Stevaux, O. & Dyson, N. J. A revised picture of the E2F transcriptional network and RB function. _Curr.

Opin. Cell Biol._ 14, 684–691 (2002). Article  CAS  PubMed  Google Scholar  * Lipinski, M. M. & Jacks, T. The retinoblastoma gene family in differentiation and development. _Oncogene_

18, 7873–7882 (1999). Article  CAS  PubMed  Google Scholar  * Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. _Genes Dev._ 13,

1501–1512 (1999). Article  CAS  PubMed  Google Scholar  * Sherr, C. J. Principles of tumor suppression. _Cell_ 116, 235–246 (2004). Article  CAS  PubMed  Google Scholar  * Geng, Y. et al.

Rescue of cyclin D1 deficiency by knockin cyclin E. _Cell_ 97, 767–777 (1999). Article  CAS  PubMed  Google Scholar  * Kozar K et al. Mouse development and cell proliferation in the absence

of d-cyclins. _Cell_ 118, 477–491, (2004). Article  CAS  PubMed  Google Scholar  * Malumbres, M. et al., Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6.

_Cell_ 118, 493–504, (2004). Article  CAS  PubMed  Google Scholar  * Pavletich, N. P. Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip

and INK4 inhibitors. _J. Mol. Biol._ 287, 821–828 (1999). Article  CAS  PubMed  Google Scholar  * Blain, S. W., Scher, H. I., Cordon-Cardo, C. & Koff, A. p27 as a target for cancer

therapeutics. _Cancer Cell_ 3, 111–115 (2003). Article  CAS  PubMed  Google Scholar  * Montagnoli, A. et al. Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric

complex formation. _Genes Dev._ 13, 1181–1189 (1999). Article  CAS  PubMed  PubMed Central  Google Scholar  * Reed, S. I. Ratchets and clocks: the cell cycle, ubiquitylation and protein

turnover. _Nature Rev. Mol. Cell. Biol._ 4, 855–864 (2003). Article  ADS  CAS  Google Scholar  * Bashir, T., Dorrello, N. V., Amador, V., Guardavaccaro, D. & Pagano, M. Control of the

SCF (Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. _Nature_ 428, 190–193 (2004). Article  ADS  CAS  PubMed  Google Scholar  * Wei, W. et al. Degradation of the SCF

component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. _Nature_ 428, 194–198 (2004). Article  ADS  CAS  PubMed  Google Scholar  * Petronczki, M., Siomos, M. F. &

Nasmyth, K. Un menage a quatre: the molecular biology of chromosome segregation in meiosis. _Cell_ 112, 423–440 (2003). Article  CAS  PubMed  Google Scholar  * Rape, M. & Kirschner, M.

W. Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry. _Nature_ (in the press). * Hsu, J. Y. et al. E2F-dependent accumulation of hEmi1 regulates S

phase entry by inhibiting APC (Cdh1). _Nature Cell Biol._ 4, 358–366 (2002). Article  CAS  PubMed  Google Scholar  * Yu, Q., Geng, Y. & Sicinski, P. Specific protection against breast

cancers by cyclin D1 ablation. _Nature_ 411, 1017–1021 (2001). Article  ADS  CAS  PubMed  Google Scholar  * Pawson, T. Specificity in signal transduction: from phosphotyrosine-SH2 domain

interactions to complex cellular systems. _Cell_ 116, 191–203 (2004). Article  CAS  PubMed  Google Scholar  * Schlessinger, J. & Lemmon, M. A. SH2 and PTB domains in tyrosine kinase

signaling. _Sci. STKE_ 191, RE12 (2003). Google Scholar  * Downward, J. Targeting RAS signalling pathways in cancer therapy. _Nature Rev. Cancer_ 3, 11–22 (2003). Article  CAS  Google

Scholar  * Coleman, M. L., Marshall, C. J. & Olson, M. F. RAS and RHO GTPases in G1-phase cell-cycle regulation. _Nature Rev. Mol. Cell Biol._ 5, 355–366 (2004). Article  CAS  Google

Scholar  * Giancotti, F. G. & Tarone, G. Positional control of cell fate through joint integrin/receptor protein kinase signaling. _Annu. Rev. Cell Dev. Biol._ 19, 173–206 (2003).

Article  CAS  PubMed  Google Scholar  * Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. _Nature Rev. Cancer_ 2, 489–501 (2002). Article  CAS 

Google Scholar  * Tran, H., Brunet, A., Griffith, E. C. & Greenberg, M. E. The many forks in FOXO's road. _Sci. STKE_ 172, RE5 (2003). Google Scholar  * Gschwind, A., Fischer, O. M.

& Ullrich, A. The discovery of receptor tyrosine kinases: targets for cancer therapy. _Nature Rev. Cancer_ 4, 361–370 (2004). Article  CAS  Google Scholar  * Sawyers, C. L.

Opportunities and challenges in the development of kinase inhibitor therapy for cancer. _Genes Dev._ 17, 2998–3010 (2003). Article  CAS  PubMed  Google Scholar  * Davies, H. et al. Mutations

of the BRAF gene in human cancer. _Nature_ 417, 949–954 (2002). Article  ADS  CAS  PubMed  Google Scholar  * Noble, M. E., Endicott, J. A. & Johnson, L. N. Protein kinase inhibitors:

insights into drug design from structure. _Science_ 303, 1800–1805 (2004). Article  ADS  CAS  PubMed  Google Scholar  * Arteaga, C. L. & Baselga, J. Tyrosine kinase inhibitors; why does

the current process of clinical development not apply to them? _Cancer Cell_ 5, 525–531 (2004). Article  CAS  PubMed  Google Scholar  * Ferrara, N., Hillan, K. J., Gerber, H. P. &

Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. _Nature Rev. Drug. Discov._ 3, 391–400 (2004). Article  CAS  Google Scholar  * Chiosis, G. L.

B., Huezo, H., Solit, D., Basso, A. & Rosen, N. Development of purine-scaffold small molecule inhibitors of Hsp90. _Curr. Cancer Drug Targets_ 3, 371–376 (2003). Article  CAS  PubMed 

Google Scholar  * Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. _Science_ 304, 1497–1500 (2004). Article  ADS  CAS  PubMed 

Google Scholar  * Maher, E. A. et al. Malignant glioma: genetics and biology of a grave matter. _Genes Dev._ 15, 1311–1333 (2001). Article  CAS  PubMed  Google Scholar  * Pao, W. et al. EGF

receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib (Iressa®) and erlotinib (Tarceva TM). _Proc. Natl Acad.

Sci. USA_ 101, 13306–13311 (2004). Article  ADS  CAS  PubMed  PubMed Central  Google Scholar  * Danial, N. N. & Korsmeyer, S. J. Cell death: critical control points. _Cell_ 116, 205–219

(2004). Article  CAS  PubMed  Google Scholar  * Ashkenazi, A. & Dixit, V. M. Death receptors: signaling and modulation. _Science_ 281, 1305–1308 (1998). Article  CAS  PubMed  Google

Scholar  * Jiang, X. & Wang, X. Cytochrome C-mediated apoptosis. _Ann. Rev. Biochem._ 73, 87–106 (2004). Article  CAS  PubMed  Google Scholar  * Davis, R. J. Signal transduction by the

JNK group of MAP kinases. _Cell_ 103, 239–252 (2000). Article  CAS  PubMed  Google Scholar  * Kolesnick, R. & Fuks, Z. Radiation and ceramide-induced apoptosis. _Oncogene_ 22, 5897–5906

(2003). Article  CAS  PubMed  Google Scholar  * Cory, S. & Adams, J. M. The Bcl2 family: regulators of the cellular life-or-death switch. _Nature Rev. Cancer_ 2, 647–656 (2002). Article

  CAS  Google Scholar  * Hu, M. C. et al. IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. _Cell_ 117, 225–237 (2004). Article  CAS  PubMed  Google Scholar  *

Bonni, A. et al. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. _Science_ 286, 1358–1362 (1999). Article  CAS  PubMed 

Google Scholar  * Barradas, M., Monjas, A., Diaz-Meco, M. T., Serrano, M. & Moscat, J. The downregulation of the pro-apoptotic protein Par-4 is critical for Ras-induced survival and

tumor progression. _EMBO J._ 18, 6362–6369 (1999). Article  CAS  PubMed  PubMed Central  Google Scholar  * Bjornsti, M. A. & Houghton, P. J. The TOR pathway: a target for cancer therapy.

_Nature Rev. Cancer_ 4, 335–348 (2004). Article  CAS  Google Scholar  * Lizcano, J. M. et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1.

_EMBO J._ 23, 833–843 (2004). Article  CAS  PubMed  PubMed Central  Google Scholar  * Shaw, R. J. et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. _Cancer Cell_ 6, 91–99

(2004). Article  CAS  PubMed  Google Scholar  * Holland, E. C., Sonenberg, N., Pandolfi, P. P. & Thomas, G. Signaling control of mRNA translation in cancer pathogenesis. _Oncogene_ 23,

3138–3144 (2004). Article  CAS  PubMed  Google Scholar  * Rajasekhar, V. K. et al. Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of

existing mRNAs to polysomes. _Mol. Cell_ 12, 889–901 (2003). Article  CAS  PubMed  Google Scholar  * Wendel et al. Survival signaling by Akt and eIF4E in oncogenetics and cancer therapy.

_Nature_ 428, 332–337 (2004). Article  ADS  CAS  PubMed  Google Scholar  * Ruggero, D. et al. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in

lymphomagenesis. _Nature Med._ 10, 484–486 (2004). Article  CAS  PubMed  Google Scholar  * Cohen, P. & Frame, S. The renaissance of GSK3. _Nature Rev. Mol. Cell Biol._ 2, 769–776 (2001).

Article  CAS  Google Scholar  * Jope, R. S. & Johnson, G. V. The glamour and gloom of glycogen synthase kinase-3. _Trends Biochem. Sci._ 29, 95–102 (2004). Article  CAS  PubMed  Google

Scholar  * Grandori, C., Cowley, S. M., James, L. P. & Eisenman, R. N. The Myc/Max/Mad network and the transcriptional control of cell behavior. _Annu. Rev. Cell Dev. Biol._ 16, 653–699

(2000). Article  CAS  PubMed  Google Scholar  * Wanzel, M., Herold, S. & Eilers, M. Transcriptional repression by Myc. _Trends Cell Biol._ 13, 146–150 (2003). Article  CAS  PubMed 

Google Scholar  * Seoane, J., Le, H. V. & Massagué, J. Myc suppression of the p21 (Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage. _Nature_ 419, 729–734

(2002). Article  ADS  CAS  PubMed  Google Scholar  * Pelengaris, S., Khan, M. & Evan, G. c-MYC: more than just a matter of life and death. _Nature Rev. Cancer_ 2, 764–776 (2002). Article

  CAS  Google Scholar  * Siegel, P. M. & Massagué, J. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. _Nature Rev. Cancer_ 3, 807–821 (2003). Article  CAS  Google

Scholar  * Shi, Y. & Massagué, J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. _Cell_ 113, 685–700 (2003). Article  CAS  PubMed  Google Scholar  * Seoane, J., Le,

H. V., Shen, L., Anderson, S. A. & Massagué, J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. _Cell_ 117, 211–23

(2004). Article  CAS  PubMed  Google Scholar  * Accili, D. & Arden, K. C. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. _Cell_ 117, 421–426 (2004).

Article  CAS  PubMed  Google Scholar  * Derynck, R., Akhurst, R. J. & Balmain, A. TGF-beta signaling in tumor suppression and cancer progression. _Nature Genet._ 29, 117–129 (2001).

Article  CAS  PubMed  Google Scholar  * Roberts, A. B. & Wakefield, L. M. The two faces of transforming growth factor beta in carcinogenesis. _Proc. Natl Acad. Sci. USA_ 100, 8621–8623

(2003). Article  ADS  CAS  PubMed  PubMed Central  Google Scholar  * Michael, D. & Oren, M. The p53 and Mdm2 families in cancer. _Curr. Opin. Genet. Dev._ 12, 53–59 (2002). Article  CAS

  PubMed  Google Scholar  * Sancar, A., Lindsey-Boltz, L. A., Unsal-Kaccmaz, K. & Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. _Annu. Rev.

Biochem._ 73, 39–85 (2004). Article  CAS  PubMed  Google Scholar  * Vousden, K. H. & Lu, X. Live or let die: the cell's response to p53. _Nature Rev. Cancer_ 2, 594–604 (2002).

Article  CAS  Google Scholar  * Flores, E. et al. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. _Nature_ 416, 560–564 (2002). Article  ADS  CAS  PubMed 

Google Scholar  * Senoo, M., Manis, J. P., Alt, F. W. & McKeon, F. p63 and p73 are not required for the development and p53-dependent apoptosis of T cells. _Cancer Cell_ 6, 85–89 (2004).

Article  CAS  PubMed  Google Scholar  * Brooks, C. L. & Gu, W. Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. _Curr. Opin. Cell Biol._ 15,

164–171 (2003). Article  CAS  PubMed  Google Scholar  * Lowe, S. W. & Sherr, C. J. Tumor suppression by Ink4a-Arf: progress and puzzles. _Curr. Opin. Genet. Dev._ 13, 77–83 (2003).

Article  CAS  PubMed  Google Scholar  * Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. _Science_ 303, 2011–2015 (2004). Article  ADS 

CAS  PubMed  Google Scholar  * Motta, M. C. et al. Mammalian SIRT1 represses forkhead transcription factors. _Cell_ 116, 551–563 (2004). Article  CAS  PubMed  Google Scholar  * Arden, K. C.

FoxO: linking new signaling pathways. _Mol. Cell_ 14, 416–418 (2004). Article  CAS  PubMed  Google Scholar  * So, C. W. & Cleary, M. L. MLL-AFX requires the transcriptional effector

domains of AFX to transform myeloid progenitors and transdominantly interfere with forkhead protein function. _Mol. Cell. Biol._ 22, 6542–6552 (2003). Article  CAS  Google Scholar  *

Ruzinova, M. B. & Benezra, R. Id proteins in development, cell cycle and cancer. _Trends Cell Biol._ 13, 410–418 (2003). Article  CAS  PubMed  Google Scholar  * Ying, Q. L., Nichols, J.,

Chambers, I. & Smith, A. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. _Cell_ 115, 281–292 (2003).

Article  CAS  PubMed  Google Scholar  * Jacobs, J. J. et al. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. _Genes Dev._ 13, 2678–2690

(1999). Article  CAS  PubMed  PubMed Central  Google Scholar  * Park, I. K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. _Nature_ 423, 302–305

(2003). Article  ADS  CAS  PubMed  Google Scholar  * Lessard, J. & Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. _Nature_ 423, 255–260

(2003). Article  ADS  CAS  PubMed  Google Scholar  * Owens, D. M. & Watt, F. M. Contribution of stem cells and differentiated cells to epidermal tumours. _Nature Rev. Cancer_ 3, 444–451

(2003). Article  CAS  Google Scholar  * Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. _Nature_ 414, 105–111 (2001). Article  ADS 

CAS  PubMed  Google Scholar  * Jamieson, C. H. et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. _N. Engl. J. Med._ 351, 657–667 (2004). Article

  CAS  PubMed  Google Scholar  * Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. _Proc.

Natl Acad. Sci. USA_ 100, 3983–3988 (2003). Article  ADS  CAS  PubMed  PubMed Central  Google Scholar  * van de Wetering, M. et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor

phenotype on colorectal cancer cells. _Cell_ 111, 241–250 (2002). Article  CAS  PubMed  Google Scholar  * Lum, L. & Beachy, P. A. The Hedgehog response network: sensors, switches, and

routers. _Science_ 304, 1755–1759 (2004). Article  ADS  CAS  PubMed  Google Scholar  * Oliver, T. G. et al. Transcriptional profiling of the Sonic hedgehog response: a critical role for

N-myc in proliferation of neuronal precursors. _Proc. Natl Acad. Sci. USA_ 100, 7331–7336 (2003). Article  ADS  CAS  PubMed  PubMed Central  Google Scholar  * Kerney, A. M., Cole, H. D.

& Rowitch, D. H. Nmyc upregulation by sonic hedgehog signalling promotes proliferation in developing cerebellar granule neurone precursors. _Development_ 130, 15–28 (2003). Article  CAS

  Google Scholar  * Grady, W. M. & Markowitz, S. D. Genetic and epigenetic alterations in colon cancer. _Annu. Rev. Genomics Hum. Genet._ 3, 101–128 (2002). Article  CAS  PubMed  Google

Scholar  * Berman, D. M. et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. _Nature_ 425, 846–851 (2003). Article  ADS  CAS  PubMed  Google

Scholar  * Thayer, S. P. et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. _Nature_ 425, 851–856 (2003). Article  ADS  CAS  PubMed  PubMed Central  Google

Scholar  * Karhadkar, S. S. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. _Nature_ 431, 707–712 (2004). Article  ADS  CAS  PubMed  Google Scholar  * Shah, N. P. et

al. Overriding imatinib resistance with a novel ABL kinase inhibitor. _Science_ 305, 399–401 (2004). Article  ADS  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS The

author thanks E. Holland, N. Rosen and D. Solit for helpful discussions. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Cancer Biology and Genetics Program, and Howard Hughes Medical

Institute, Box 116, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10021, USA Joan Massagué Authors * Joan Massagué View author publications You can also search for this

author inPubMed Google Scholar ETHICS DECLARATIONS COMPETING INTERESTS The author declares no competing financial interests. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS

ARTICLE CITE THIS ARTICLE Massagué, J. G1 cell-cycle control and cancer. _Nature_ 432, 298–306 (2004). https://doi.org/10.1038/nature03094 Download citation * Published: 17 November 2004 *

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