Cyclin B was one of the first two proteins originally identified as cyclin for its periodic mode of synthesis and degradation. Addition of sea urchin cyclin B mRNA to Xenopus egg extracts stimulated mitotic entry, without requiring synthesis of any other proteins. Numerous later studies confirmed the role of cyclin B as the bona fide activator of Cdk1, and B cyclins were identified in all eukaryotic organisms. Mammals have three B cyclins - B1, B2 and B3.
Cyclin B1 is a primary binding partner of Cdk1. Cyclin B1 levels rise in interphase and fall abruptly at mitotic exit. Abrupt destruction of cyclin B1 is mediated by the activity of the Anaphase Promoting Complex/Cyclosome (APC/Cyclosome). The sole catalytic partner of cyclin B1 in vivo is Cdk1, and during mitosis the largest share of the Cdk kinase activity is associated with cyclin B1.
Localization of cyclin B throughout the cell cycle is very dynamic and is thought to be important for directing the Cdk1 activity toward its substrates. In interphase, cyclin B is actively excluded from the nucleus. Actively means that even though it continuously shuttles between the nucleus and cytoplasm, its export prevails over its import. Therefore, most of the Cdk1/cyclin B complex ends up in the cytoplasm. This nuclear export is mediated by the Nuclear Export Signal sequence (NES), located in the N-terminus of the cyclin B1. This NES is a leucine-rich region that binds to the nuclear export receptor Crm1. Inactivating the NES by mutating a key hydrophobic residue needed for Crm1 interaction (F112 in Xenopus), or inhibiting Crm1 with Leptomycin B renders cyclin B1 nuclear in interphase. The mechanism of nuclear import of cyclin B1, uncovered by inhibiting its export from the nucleus, is unusual. Ordinarily, NLS-containing proteins bind to a heterodimeric receptor composed of importin α and importin β. This complex is then translocated through the nuclear pore and disassembled inside the nucleus by mechanisms that require the small GTPase Ran. However, neither cyclin B1 nor Cdk1 has a Nuclear Localization Signal (NLS) in its sequence. Also, the nuclear import of cyclin B depends at least in part on importin β, but not importin α. And finally, the disassociation of cyclin B1/importin β complex inside the nucleus is not mediated by Ran-GTP. Even though the exact mechanism of the cyclin B traffic is not completely elucidated, it is evident that the localization of cyclin B1 is controlled by outbalancing its nuclear export versus import in interphase. In the cytoplasm of interphase cells, most of the protein appears to be diffuse, with a portion of it localized on centrosomes and microtubules.
Cyclin B2 is expressed together with cyclin B1 in a majority of proliferating tissues and in cultured cells. Like cyclin B1, cyclin B2 can bind and activate Cdk1. Unlike cyclin B1, cyclin B2 is not essential for the mammalian embryonic development. Mice lacking cyclin B2 are viable and display no obvious phenotype. However, the ex
In interphase cells, cyclin B2 is localized primarily to the Golgi apparatus. In mitosis, when the Golgi disassembles, cyclin B2 becomes dispersed in the cytoplasm. Even though the N-terminus of cyclin B2 harbors a functional NES, its significance is not clear because the protein is not detectable in the nucleus in the presence of Leptomycin B. The evidence for the nuclear translocation of cyclin B2 in prophase are somewhat conflicting. Early studies from Erich Nigg’s group showed translocation of cyclin B2 into the nucleus in prophase. This group expressed avian cyclin B2 in HeLa cells and labeled the endogenous human protein with the antibody raised against the avian cyclin B2. Jon Pines’s group later showed that the human cyclin B2 does not translocate into the nucleus in prophase, both by antibody labeling and by overex
Cyclin B3 is the least explored of B cyclins. Its physiological function is completely unknown. In mammals, it is expressed mostly in developing germ cells and adult testis, perhaps suggesting some relationship to meiosis. It is expressed ubiquitously in avians, worms and flies. However, D melanogaster and C elegance cyclin - B3 is very distinct from the mammalian B3.
Mammalian cyclin B3 has a longer sequence than any other cyclin (1395aa in human) due to an additional unique sequence in its N-terminus. Several isoforms were identified in tissues by reverse transcription - PCR (RT-PCR). They differ from each other in their subcellular localization when expressed ectopically. However, the endogenous proteins in these studies were not readily detectable. When ectopically expressed in tissue culture cells, cyclin B3 can bind Cdks 1 and 2, and like other B cyclins is degraded during the M to G1 transition. The evidence of the ability of cyclin B3 to activate either one Cdk is scarce, but the fact that the non-degradable version of cyclin B3 blocks the M to G1 transition like other B cyclins suggests that it can activate Cdk1. Interestingly, the non-degradable cyclin B3 reportedly blocks the G1/S transition also, which is difficult to explain. It would be very interesting to know if the cyclin B3, when overexpressed, can compensate for the loss of cyclins B1 and B2.