The biology behind the name

In 1971 Masui and Markert found that cytoplasm taken from a mature frog egg makes an immature egg enter division. They called the active substance the maturation-promoting factor. It later turned out to be the same in yeast, frogs and humans: a cyclin-dependent kinase (CDK) bound to a cyclin (Nurse 1990). The CDK is the catalytic subunit. It adds phosphate groups to hundreds of target proteins. The cyclin is the regulatory subunit: the CDK is inactive without it, and the cyclin decides which targets are phosphorylated.

Different cyclin–CDK pairs act in successive phases (Figure 2). Cyclin D–CDK4/6 responds to growth signals and phosphorylates the retinoblastoma protein (Rb), which releases the genes needed for DNA replication. Cyclin E–CDK2 commits the cell to S phase. Cyclin A–CDK2 completes replication. Cyclin B–CDK1, the MPF itself, starts mitosis: chromosome condensation, breakdown of the nuclear envelope and assembly of the spindle. MPF is held inactive by the kinase Wee1, which phosphorylates CDK1 on tyrosine 15. It is switched on abruptly when the phosphatase Cdc25 removes that phosphate. Because active MPF also activates Cdc25 and inhibits Wee1, entry into mitosis works like an all-or-none switch.

Cyclin destruction: a biochemical oscillator

Cells break down proteins in two main ways. Long-lived proteins and whole organelles are digested in lysosomes, acidic compartments (pH about 4.5–5) filled with hydrolytic enzymes. Short-lived regulatory proteins, including cyclins, are destroyed in the near-neutral cytosol (pH about 7.2) by the ubiquitin–proteasome system. Ubiquitin is a small protein of 76 amino acids (about 8.6 kDa). A chain of ubiquitin molecules attached to a protein marks it for destruction by the proteasome.

Cyclin B carries a short sequence of about nine amino acids near its N-terminus, the destruction box. At the transition from metaphase to anaphase, an enzyme complex called the anaphase-promoting complex/cyclosome (APC/C), together with its activator Cdc20, recognises this box and attaches ubiquitin. Cyclin B is then destroyed within minutes, MPF activity collapses, and the cell can separate its chromosomes and divide (Glotzer et al. 1991). Synthesis followed by abrupt destruction makes cyclin levels rise and fall once per cycle (Figure 3). This is why the cell-cycle control system is described as a biochemical oscillator.

The brakes: p53 and the CDK inhibitors

Two families of proteins inhibit cyclin–CDK complexes (Sherr & Roberts 1999). They are regulators of the cyclins, not parts of them.

• CIP/KIP family (p21, p27, p57). The tumour suppressor p53, often called the guardian of the genome, accumulates after DNA damage. It switches on the gene for p21, which blocks CDK2 and CDK1 and stops the cycle until the damage is repaired or the cell is eliminated (el-Deiry et al. 1993). p21 also rises in ageing (senescent) cells. p27 links contact inhibition and transforming growth factor-β (TGF-β) to arrest of the cycle: cells that touch their neighbours stop dividing (Polyak et al. 1994).
• INK4 family (p16, p15, p18, p19). These proteins bind CDK4 and CDK6 and prevent them from pairing with cyclin D. p15 is induced by TGF-β and helps mediate its growth-inhibiting effect (Hannon & Beach 1994). p16 is one of the genes most frequently lost in human cancers.

Heat-shock proteins also take part. The chaperone Hsp90, together with its partner Cdc37, binds and stabilises CDK4 (Stepanova et al. 1996). Sustained proliferative signalling and evasion of growth suppressors are two of the recognised hallmarks of cancer (Hanahan & Weinberg 2011). The role of CDKs in cancer is reviewed by Malumbres & Barbacid (2009). Drugs that inhibit CDK4/6 (palbociclib, ribociclib, abemaciclib) are now a standard part of the treatment of hormone-receptor-positive advanced breast cancer.

How cell proliferation is measured directly

No blood test measures MPF activity. The reference methods are invasive: they need a sample of tissue obtained by biopsy or surgery. The pathologist counts mitotic figures under the microscope, a key element of tumour grading. Staining for the Ki-67 protein, which is present only in cycling cells, gives the proportion of proliferating cells and is used, for example, in breast cancer (Dowsett et al. 2011). Flow cytometry of DNA content shows the fraction of cells in S phase. The Kolibri index is an estimate obtained from the method's physiological model. It is not a laboratory measurement of these markers.

Interpretation in this application

References

1. Masui Y, Markert CL. Cytoplasmic control of nuclear behavior during meiotic maturation of frog oocytes. J Exp Zool. 1971;177(2):129–145. doi:10.1002/jez.1401770202
2. Nurse P. Universal control mechanism regulating onset of M-phase. Nature. 1990;344(6266):503–508. doi:10.1038/344503a0
3. Glotzer M, Murray AW, Kirschner MW. Cyclin is degraded by the ubiquitin pathway. Nature. 1991;349(6305):132–138. doi:10.1038/349132a0
4. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13(12):1501–1512. doi:10.1101/gad.13.12.1501
5. el-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75(4):817–825. doi:10.1016/0092-8674(93)90500-P
6. Polyak K, Kato JY, Solomon MJ, et al. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994;8(1):9–22. doi:10.1101/gad.8.1.9
7. Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-β-induced cell cycle arrest. Nature. 1994;371(6494):257–261. doi:10.1038/371257a0
8. Stepanova L, Leng X, Parker SB, Harper JW. Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev. 1996;10(12):1491–1502. doi:10.1101/gad.10.12.1491
9. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9(3):153–166. doi:10.1038/nrc2602
10. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi:10.1016/j.cell.2011.02.013
11. Dowsett M, Nielsen TO, A'Hern R, et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer Working Group. J Natl Cancer Inst. 2011;103(22):1656–1664. doi:10.1093/jnci/djr393

This article is for general information and does not replace a consultation with a doctor. Measurements must be interpreted by a physician together with symptoms and other tests.