TITULO II ENTORNO SOCIAL QUE RODEA A LA EMPRESA
6.3 Aspectos sociales que repercuten en la Micro y Pequeña Empresa
As discussed under therapeutic strategies in Chapter 2 (see “Organic drugs”), some conventional chemotherapies interfere with microtubule formation and spindle formation. Paclitaxel/taxol stabilize micro tubules while the vinca alkaloids (vinblastine, vincristine) inhibit microtubule assembly. These drugs result in chromatid pairs that are not attached to spindle fi bers and thus activate the mitotic checkpoint. It is thought that the mechanism of action of these drugs is cytostatic, but induction of
• The cell cycle is made up of four phases: G1, S, G2, and M.
• There are three cell cycle checkpoints: the G1, G2, and M checkpoints.
• The progression of a cell through the different phases of the cell cycle is highly regulated by cyclins and cyclin-dependent kinases (cdks).
• Cdks are regulated by association with cyclins, inhibitors, and by activating and inhibitory phosphorylation.
• Proteolysis is important for regulating the activity of key regulators of the cell cycle.
• The retinoblastoma (RB) protein is an important target of cyclin D–cdks 4/6 and a key regulator of the G1 to S phase transition.
• RB exerts its effects by protein–protein interactions with the E2F transcription factor and HDACs.
• The activity of RB is regulated by phosphorylation via dif-ferent cyclins–cdks.
• Hypophosphorylated RB inactivates E2F and recruits HDACs.
• Phosphorylated RB releases E2F and HDACs, which facili-tates transcription and cell cycle progression into S phase.
• The G2 checkpoint is induced by DNA damage and aber-rant DNA synthesis and blocks entry into M phase.
• The mitotic checkpoint prevents mis-segregation of chro-mosomes during anaphase.
• Aurora kinases are important for centrosome and mitotic spindle function.
• Aberrant regulation of the cell cycle can lead to cancer.
• Cyclin D amplifi cation often occurs in breast cancer and squamous cell carcinoma.
• Several cdk inhibitors have entered clinical trials.
• Several conventional chemotherapies exert their effects by activating the mitotic checkpoint.
■ CHAPTER HIGHLIGHTS—REFRESH YOUR MEMORY
apoptosis may also be a consequence. A molecule called KSP, an ATP-dependent microtubule-motor protein, is required for spindle pole separa-tion and is a new molecular target for the development of cancer therapies.
A small-molecule inhibitor of KSP called ispinesib (Cytokinetics) prevents mitotic spindle pole separation and also leads to chronic mitotic check-point activation and is being tested in multiple Phase I and II trials. Thus far, it shows a favorable safety profi le and a 9% response rate in patients with advanced or metastatic breast cancer.
■ ACTIVITY
1. Critically discuss your views on whether you would carry out research on cdk inhibitors, and if so what strategy would you use. Support your view with pre-clinical and clinical evi-dence.
2. It has been stated in this chapter that ubiquitin-mediated proteolysis is crucial for regula-tion of the cell cycle. Find evidence that supports the statement that unregulated proteol-ysis in the cell cycle can lead to cancer. Begin with the paper by Reed (2003).
■ FURTHER READING
Burkhart, D.L. and Sage, J. (2008) Cellular mechanisms of tumor suppression by the retinoblastoma gene. Nature Rev. Cancer 8: 671–682.
Chinnam, M. and Goodrich, D.W. (2011) RB1, development, and cancer. Curr. Topics Devel. Biol. 94: 129–169.
Collins, I. and Garrett, M.D. (2005) Targeting the cell division cycle in cancer: CDK and cell cycle checkpoint kinase inhibitors. Curr. Opin. Pharmacol. 5: 366–373.
DiCiommo, D., Gallie, B.L., and Bremner, R. (2000) Retinoblastoma: the disease, gene and protein provide critical leads to understand cancer. Semin. Cancer Biol. 10:
255–269.
Kaufmann, W.K. (2006) Dangerous entanglements. Trends Mol. Med. 12: 235–237.
Kops, G.J.P.L., Weaver, B.A.A., and Cleveland, D.W. (2005) On the road to cancer:
aneuploidy and the mitotic checkpoint. Nature Rev. Cancer 5: 773–785.
Lapenna, S. and Giordano, A. (2009) Cell cycle kinases as therapeutic targets for can-cer. Nature Rev. Drug Discov. 8: 547–566.
Malumbres, M. and Barbacid, M. (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nature Rev. Cancer 9: 153–166.
Massagué, J. (2004) G1 cell-cycle control and cancer. Nature 432: 298–306.
Meraldi, P., Honda, R., and Nigg, E.A. (2004) Aurora kinases link chromosome segre-gation and cell division to cancer susceptibility. Curr. Opin. Genet. Dev. 14: 29–36.
Shah, M.A. and Schwartz, G.K. (2006) Cyclin dependent kinases as targets for cancer therapy. Update Cancer Ther. 1: 311–332.
Sherr, C.J. and Roberts, J.M. (2004) Living with or without cyclins and cyclin-depend-ent kinases. Genes Devel. 18: 2699–2711.
Swanton, C. (2004) Cell-cycle targeted therapies. Lancet Oncol. 5: 27–36.
Weaver, B.A.A. and Cleveland, D.W. (2005) Decoding the links between mitosis, can-cer and chemotherapy: the mitotic checkpoint, adaptation, and cell death. Cancan-cer Cell 8: 7–12.
Zhu, L. (2005) Tumour suppressor retinoblastoma protein Rb: a transcriptional regu-lator. Eur. J. Cancer 41: 2415–2427.
■ SELECTED SPECIAL TOPICS
Emanuel, S., Rugg, C.A., Gruninger, R.H., Lin, R., Fuentes-Pesquera, A., Connolly, P.J., et al. (2005) The in vitro and in vivo effects of JNJ-7706621: A dual inhibitor of cyclin-dependent kinases and aurora kinases. Cancer Res. 65: 9038–9046.
Ewart-Toland, A., Briassouli, P., de Koning, J.P., Mao, J.-H., Yuan, J., Chan, F., et al.
(2003) Identifi cation of Stk6/STK15 as a candidate low-penetrance tumor-suscepti-bility gene in mouse and human. Nature Genet. 34: 403–412.
Musgrove, E.A., Caldon, C.E., Barraclough, J., Stone, A., and Sutherland, R.L. (2011) Cyclin D as a therapeutic target in cancer. Nature Rev. Cancer 11: 558–572.
Reed, S.I. (2003) Ratchets and clocks: the cell cycle, ubiquitylation and protein turn-over. Nature Rev. Mol. Cell Biol. 4: 855–864.
Roy, P.G. and Thompson, A.M. (2006) Cyclin D1 and breast cancer. Breast 15:
718–727.
Rubin, S.M., Gall, A.-L., Zheng, N., and Pavletich, N.P. (2005) Structure of the Rb C-terminal domain bound to E2F-DP1: A mechanism for phosphorylation-induced E2F release. Cell 123: 1093–1106.
Sanchez, I. and Dynlacht, B.D. (2005) New insights into cyclins, CDKs, and cell cycle control. Semin. Cell Dev. Biol. 16: 311–321.
Senderowicz, A.M. (2003) Small-molecule cyclin-dependent kinase modulators.
Oncogene 22: 6609–6620.
Sharpless, N.E., Bardeesy, N., Lee, K.H., Carrasco, D., Castrillon, D.H., Aguirre, A.J., et al. (2001) Loss of p16Ink4a with retention of p19Arf predisposes mice to tumori-genesis. Nature 413: 86–91.
Utikal, J., Udart, M., Leiter, U., Kaskel, P., Peter, R.U., and Krahn, G. (2005) Numeri-cal abnormalities of the Cyclin D1 gene locus on chromosome 11q13 in non-mela-noma skin cancer. Cancer Lett. 219: 197–204.