This group represents the cyclin-dependent kinase 2-associated protein 1/2 (DOC-1/1R). DOC-1 is a specific inhibitor of the cell-cycle kinase CDK2 []. DOC-1R associates with CDK2 and inhibits CDK2 activation by obstructing its association with cyclin E and A [].
Speedy (Spy1, also known as RINGO A) is a cell cycle regulatory protein which binds and activates CDK1 and CDK2 [], protein kinases that allows progression through G1/S phase and further replication events. Spy1 activates CDK2 inducing a conformational change of the CDK2 T-loop that avoids its phosphorylation []. Spy1 expression overcomes a p27-induced cell cycle arrest to allow for DNA synthesis, so cell cycle progression occurs due to an interaction between Spy1 and p27 [].
Cyclin-dependent kinase 2-interacting protein (CINP) is a component of theactive cyclin E/Cdk2 and cyclin A/Cdk2 complexes []. It is phopshorylated by Cdc7, but not by Cdk2 []. CINP has also been shown to bind to chromatin in a replication-dependent manner, and to associate with Origin Recognition Complex-2 (ORC2)-containing complexes and minichromosome maintenance/DNA replication licensing complex, MCM []. It has been proposed that CINP is part of the Cdc7-dependent mechanism of origin firing, and constitutes a physical link between Cdk2 and Cdc7 complexes at the origins [].
PURgamma belongs to the purine-rich element binding (PUR) protein family, which consists of PURalpha, PURbeta and PURgamma. Purgamma colocalises with Cdk2 to a specific DNA segment upstream of the c-MYC gene []. It also has been detected upstream of the gene encoding the Werner syndrome helicase, Wrn, at human chromosome band 8p11-12 [].
This entry represents a domain found in cyclin-dependent kinase inhibitor 3 or kinase associated phosphatase proteins from several mammalian species. The cyclin-dependent kinase (Cdk)-associated protein phosphatase (KAP) is a human dual specificity protein phosphatase that dephosphorylates Cdk2 on threonine 160 in a cyclin-dependent manner [, ]. This domain is also found in MAP kinase phosphatase and esterases.This entry contains both eukaryotic and bacterial proteins.
Membrane-spanning 4-domains subfamily A member 3 (MS4A3), also known as HTm4, is an hematopoietic modulator for the G1-S cell cycle transition []. HTm4 binds to the Cdk-associated Phosphatase (KAP)-Cdk2-Cyclin A complex, triggering the dissociation of cyclin A and facilitating dephosphorylation of Cdk2 by KAP [, ].
This family consists of cyclin-dependent kinase inhibitor 3 or kinase associated phosphatase proteins from several mammalian species. The cyclin-dependent kinase (Cdk)-associated protein phosphatase (KAP) is a Homo sapiens dual specificity protein phosphatase that dephosphorylates Cdk2 on threonine 160 in a cyclin-dependent manner [, ].
This family of proteins includes BRCA2 and CDKN1A-interacting protein (BCCIP) and Bcp1. In fungi, Bcp1 is involved in nuclear export, actin cytoskeleton organisation and vesicular transport []. Its homologue in human and mouse, BCCIP, may promote cell cycle arrest by enhancing the inhibition of CDK2 activity by CDKN1A/p21 and may be required for repair of DNA damage by homologous recombination in conjunction with BRCA2 [, , , ].
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles, and regulate cyclin dependent kinases (CDKs) [].This entry represents cyclin-O. In mouse oocytes, it regulates maturation-promoting factor (MPF), which affects oocyte meiotic resumption []. It is required to activate Cdk2 during apoptosis induced by intrinsic stimuli in lymphoid cells []. Its activity is modulated by p53 and members of the Bcl-2 protein family []. This entry also includes cyclin-O protein A/B, also known as CCNO, from Xenopus laevis. Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia [].
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.This entry represents cyclin E from vertebrates. Cyclin E is essential for the control of the cell cycle at the G1/S (start) transition [].
In eukaryotes, initiation of DNA replication requires the assembly of pre-replication complexes (pre-RCs) on chromatin during the G1 phase. In the S phase, pre-RCs are activated by two protein kinases, Cdk2 and Cdc7, which results in the loading of replication factors and the unwinding of replication origins by the MCM helicase complex []. Cdc7 is a serine/threonine kinase that is conserved from yeast to human. It is regulated by its association with a regulatory subunit, the Dbf4 protein. This complex is often referred to as DDK (Dbf4-dependent kinase) [].DBF4 contains an N-terminal BRCT domain and a C-terminal conserved region that could potentially coordinate one zinc atom, the DBF4-type zinc finger. This entry represents the zinc finger, which is important for the interaction with Cdc7 [, ].
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [].Cyclins contain two domains of similar all-α fold, of which this entry is associated with the N-terminal domain.
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [].This is the C-terminal domain of cyclins.
This entry represents a G1-class of cyclins which has so far only been identified in fungi [, ]. These proteins are important for the control of the cell cycle at the G1/S transition and interact with the cdc2 protein kinase.Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [].
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [].
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.Cyclin homologues have been found in various viruses, includingSaimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [].This entry includes cyclin PHO80 and other cyclins that partner with the cyclin-dependent kinase (CDK) PHO85. The PHO80/PHO85 cyclin-cdk complex is used for a regulatory process other than cell-cycle control []. This entry also includes other PHO80-like cyclins that are involved in the cell-cycle control. They belong to the P/U family and interact preferentially with CDKA1 [].
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [].This group represents a predicted cyclin found in epsilon-retroviruses, including walleye epidermal hyperplasia virus and walleye dermal sarcoma virus (WDSV).
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [].This group represents cyclin Y (also known as cyclin X) and related cyclins. Cyclin Y is a positive regulatory subunit of the cyclin-dependent kinase CDK14/PFTK1. Cyclin Y acts as a cell-cycle regulator of Wnt signaling pathway during G2/M phase by recruiting CDK14/PFTK1 to the plasma membrane and promoting phosphorylation of LRP6, leading to the activation of the Wnt signaling pathway [, ].
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [].This group represents a viral cyclin.
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). Thereare two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [].This domain adopts a secondary structure consisting of a five α-helix cyclin fold. Interaction with cyclin dependent kinases (CDKs) at a PSTAIRE sequence motif within the catalytic cleft of CDK results in the regulation of CDK activity [].
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [].This entry represents a domain found in a family of viral cyclins that specifically activate CDK6 of host cells to a very high degree []. This domain adopts a helical structure consisting of five α-helices, with one helix surrounded by the others.
Cyclin-dependent kinase 7 (CDK7) is a serine/threonine kinase involved in cell cycle control and in RNA polymerase II-mediated RNA transcription. It is activated by binding to a cyclin; binding to a different cyclin and phosphorylation of another kinase progresses the cell cycle. CDK7 binds cyclin-B and phosphorylates CDK1 during G2-M transition, and phosphorylates CDK2 and binds to cyclins during G1-S transition [, ]. CDK7 phosphorylates and activates p53 following DNA damage [], but CDK7 is then inactivated by p53, which arrests the cell cycle, allowing the cell to recover or undergo apoptosis []. CDK7 is also the catalytic subunit of the CDK-activating kinase (CAK) complex, which also contains cyclin-H (CCNH) and MAT1 [, ]. In turn, the CAK associates with the core-TFIIH to form the TFIIH basal transcription factor [].This entry includes CDK7 from animals, Kin28 from budding yeasts and Crk1 (also known as Mcs6) from fission yeasts. S. pombe possesses two CAKs, the nonessential Csk1 and the essential Mcs6 kinases, corresponding to the yeast Cak1 and the metazoan CDK7, respectively. Mcs6 modulates gene expression through both its CAK and CTD kinase activities []. Kin28 is the closest homologue of CDK7 from budding yeasts. It forms a complex with Ccl1 and Tfb3. This complex associate with TFIIH for transcription regulating activity, but does not display CAK activity []. Instead, Cak1, a single-subunit kinase distantly related to Cdk, catalyzes Cdk activation at both transitions of the budding yeast cell cycle [].
P53 is a tumor suppressor gene product; mutations in p53 or lack of expression are found associated with a large fraction of all human cancers. P53 is activated by DNA damage and acts as a regulator of gene expression that ultimatively blocks progression through the cell cycle. P53 binds to DNA as a tetrameric transcription factor. In its inactive form, p53 is bound to the ring finger protein Mdm2, which promotes its ubiquitinylation and subsequent proteosomal degradation. Phosphorylation of p53 disrupts the Mdm2-p53 complex, while the stable and active p53 binds to regulatory regions of its target genes, such as the cyclin-kinase inhibitor p21, which complexes and inactivates cdk2 and other cyclin complexes [, , , , , , , , , ].This domain is found in p53 transcription factors, where it is responsible for DNA-binding. The DNA-binding domain acts to clamp, or in the case of TonEBP, encircle the DNA target in order to stabilise the protein-DNA complex []. Protein interactions may also serve to stabilise the protein-DNA complex, for example in the STAT-1 dimer the SH2 (Src homology 2) domain in each monomer is coupled to the DNA-binding domain to increase stability []. The DNA-binding domain consists of a β-sandwich formed of 9 strands in 2 sheets with a Greek-key topology. This structure is found in many transcription factors, often within the DNA-binding domain.
Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates [, , , , ]. Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domainsare often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few []. Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target. In eukaryotes, initiation of DNA replication requires the assembly of pre-replication complexes (pre-RCs) on chromatin during the G1 phase. In the S phase, pre-RCs are activated by two protein kinases, Cdk2 and Cdc7, which results in the loading of replication factors and the unwinding of replication origins by the MCM helicase complex []. Cdc7 is a serine/threonine kinase that is conserved from yeast to human. It is regulated by its association with a regulatory subunit, the Dbf4 protein. This complex is often referred to as DDK (Dbf4-dependent kinase) [].DBF4 contains an N-terminal BRCT domain and a C-terminal conserved region that could potentially coordinate one zinc atom, the DBF4-type zinc finger. This entry represents the zinc finger, which is important for the interaction with Cdc7 [, ].
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms ofG1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [].Cyclin B3 is conserved from Caenorhabditis elegans to Homo sapiens (Human) and has an undefined meiotic function in female, but not male Drosophila melanogaster (Fruit fly). Cyclin B3 interacts with cdk2, is localised to the nucleus, and is degraded during anaphase entry after the degradation of cyclin B1. Degradation is dependent on sequences conserved in a destruction box motif. Over expression of nondegradable cyclin B3 blocks the mitotic cell cycle in late anaphase, and at higher doses it can interfere with progression through G(1) and entry into S phase. The expression pattern of mammalian cyclin B3 suggests that it may be important for events occurring in early meiotic prophase I [].In vertebrates, cyclins B1 and B2 function during M phase, whereas cyclin A is required for S phase as well as the G2 to M phase transition. The assignment of cyclin B3 to the B-type subfamily is based on cDNA-derived sequence and its pattern of expression in synchronised cells, both suggesting a distant relationship to other B-type cyclins. Interestingly, however, cyclin B3 also displays properties that resemble those of A- rather than B-type cyclins [].
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [].Among G1 regulators, D-type cyclins serve as targets of growth factors to integrate extracellular signals into the core cell cycle regulators. D-type cyclins were identified in three independent approaches; (I) a target gene of chromosomal translocations in a variety of cancers [], (II) a mammalian cyclin gene that can complement yeast G1 cyclin deficiency [], and (III) a delayed early growth factor inducible gene []. D-type cyclins are composed of three different but closely related subfamilies (D1, D2, and D3), all differentially expressed in a wide variety of organs and in a tissue-specific manner. Expression of D-type cyclins is induced in response to a variety of mitogenic signals and they function as a regulatory subunit of cyclin-dependent kinases (Cdk).D-type cyclins can interact with 4 different Cdks (Cdk2, 4, 5, and 6), among which Cdk4 and Cdk6 are apparently the major functional catalytic partners in proliferating cells. When cells are exposed to growth factor stimulation, the expression of cyclin D is maintained regardless of the point in the cell cycle. However, accumulation of active cyclin D/Cdk4 (or Cdk6) complex is rate-limiting and is required for cells to progress through G1 and to commit to entering S phase. The over expression of D-type cyclins shortens the length of G1 without affecting remainder of the cell cycle. This event is clearly different from phenotype of the cells over expressing another G1 cyclin, cyclin E, in which G1 is shortened but elongation of the S phase compensates this shortening and as a result, doubling time of the cell remains unchanged. Thus, the cyclin D/Cdk4 complex largely exerts effects on commitment of cells for the S phase entry during the G1 phase, while functions of cyclin E/Cdk2 kinase are more directly involved in the initiation of chromosomal DNA synthesis [, ].This entry is comprised of D-type cyclins that are evolutionarily conserved across a variety of species.
