Cyclins

 From a simple start as a family of proteins with interesting patterns of accumulation during the cell cycle, the cyclins have grown to become key regulators of diverse cellular processes, in particular the cell cycle. Most cyclins, whether they are present only at specific times during the cell cycle or constitutively, exert their functions through their associated cyclin-dependent kinase (Cdk) binding partners. Binding to cyclins is one of the required steps in the activation of Cdks. The degradation of many cyclins by the ubiquitin system provides a means of inactivating the associated Cdk following completion of its function. A large number of cyclins have been identified including some, like the original cyclins, that have roles in cell cycle progression, and others that don't cycle and that activate Cdks involved in very different activities, such as transcription.

 The first cyclins were found during studies of translational control before and after fertilization of sea urchin eggs conducted as part of the Physiology course at the Marine Biological Laboratory in Woods Hole (1). These proteins were synthesized continuously, and accumulated until their abrupt degradation during mitosis. This sawtooth pattern of accumulation hinted that cyclins might play an important role during the cell cycle, either as inducers of cell cycle transitions or, perhaps less interestingly, as proteins that responded to cell cycle states to perform functions important for that stage. Later work showed that the injection of cyclin mRNA caused frog oocytes to mature into eggs (2), that is, to progress through meiosis and to arrest in second meiotic metaphase, ready for fertilization. This result suggested that cyclins were actually inducers of the transitions into meiosis and mitosis. Subsequent work revealed that the mitotic cyclins are the regulatory subunits of maturation promoting factor (MPF) (3, 4). MPF had been characterized as a proteinaceous activity that, when withdrawn from the cytoplasm of an egg and injected into an oocyte, caused that oocyte to mature into an egg. The catalytic subunit of Xenopus MPF had recently been determined to be Cdc2, a protein kinase first identified by genetic studies in the fission yeast Schizosaccharomyces pombe as the key regulator of the G2-M phase transition. The following years rapidly revealed large families of proteins showing sequence similarity to the original, mitotic cyclins, and to Cdc2. The cyclins are referred to by letter (cyclin A, cyclin B, ¼) and the kinase partners have been called cyclin-dependent kinases (Cdk2, Cdk3¼).  

One of the irreversible ratchet steps in the cell cycle is the degradation of cyclins by the ubiquitin system (5). Ubiquitin is a 76-aa protein whose covalent attachment to proteins can target them for proteolysis by the proteasome, a huge multiprotease unwinding and degrading machine. Ubiquitin is activated by its ATP-dependent covalent attachment to a cysteine side chain on an enzyme called E1. E1 then transfers ubiquitin to a cysteine of one of many E2 enzymes. The E2s can ubiquitinate substrates, often with the help of an E3. The E3s may be the most diverse and interesting components of this system. Some E3s receive the covalently bound ubiquitin; others serve as matchmakers that bring together a substrate and the appropriate E2. For the mitotic cyclins, the E3 was first termed the cyclosome, though it is now generally termed the anaphase promoting complex) APC), which consists of 8 to 12 subunits. The APC is the regulated component of the ubiquitin system for the degradation of the mitotic cyclins and serves as the target for checkpoint signals that can block cyclin degradation. Proteolysis of cyclins that act earlier in the cell cycle has been best studied in the budding yeast S. cerevisiae and, though mediated by the ubiquitin system, uses an “SCF complex” as the E3 component, rather than the APC.

The cyclins now comprise a large family of proteins with diverse functions, each bound to a cyclin-dependent kinase (Cdt) catalytic partner. All cyclins resemble the first mitotic cyclins (cyclin A and B) in sequence, but not all cycle during the cell cycle. Cyclins A, B, D, and E play major roles in regulating cell cycle transitions. The cell cycle stage at which each kinase functions is largely determined by when each cyclin partner accumulates during the cell cycle. Quite a few cyclins (and their associated Cdks) function in transcription. For instance, cyclin H is one of the subunits of TFIIH, a general transcription factor for RNA polymerase II involved in the phosphorylation of the C-terminal domain (CTD) of the large subunit of the polymerase. Cyclin C is a subunit of the RNA polymerase II holoenzyme, which can also phosphorylate the CTD. As more cyclins are discovered (and the alphabet is exhausted!) the majority of all cyclins will probably be noncycling regulatory subunits of protein kinases functioning in processes other than the cell cycle. The observation that the first cyclins had cyclic patterns of accumulation and were involved in cell cycle control may represent more a historical footnote owing to their relative ease of discovery than a reflection of fundamental properties of this family of proteins.

Direct roles of cellular cyclins in diseases are extremely rare. For instance, some tumor cells contain cyclin gene amplifications. Many tumors overexpress cyclin messenger RNAs, presumably a secondary consequence of increased rates of cell proliferation. Much more important, however, is the general circumvention of normal cell cycle controls that is a hallmark of cancers. This topic is discussed in Cell Cycle. Interestingly, some viruses have co-opted cyclins to subvert normal cell cycle controls (6). For instance, the Kaposi Sarcoma Associated Herpesvirus encodes a D-type cyclin. Following infection, this cyclin associates with Cdk6, which is involved in progression through the G1 phase of the cell cycle, and activates it in a manner that makes it resistant to Cdk inhibitor proteins that normally restrain G1 progression. The infected cell is thereby pushed into S phase, allowing the virus to replicate and to produce progeny virus. This situation provides yet another example of how viruses have adapted normal cellular proteins for their own ends.

References

1. T. Evans, E. T. Rosenthal, J. Youngblom, D. Distel, and T. Hunt (1983) Cell 33, 389–396. 

2. K. I. Swenson, K. M. Farrell, and J. V. Ruderman (1986) Cell 47, 861–870. 

3. J. C. Labbé, J. P. Capony, D. Caput, J. C. Cavadore, J. Derancourt, M. Kaghad, J. M. Lelias, A. Picard, and M. Dorée (1989) EMBO J. 8, 3053–3058. 

4. J. Gautier, J. Minshull, M. Lohka, M. Glotzer, T. Hunt, and J. L. Maller (1990) Cell 60, 487–494.

5. A. M. Page and P. Hieter (1999) Annu. Rev. Biochem. 68 583–609. 

6. H. Laman, D. J. Mann, and N. C. Jones (2000) Curr. Opin. Genet. Dev. 10, 70–74.