Cyclin a Is Destroyed in Prometaphase and Can Delay Chromosome Alignment and Anaphase

Elzen, Nicole den; Pines, Jonathon

doi:10.1083/jcb.153.1.121

Cited by 344 publications

(380 citation statements)

References 63 publications

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“…Cyclin A has been detected at centrosomes although its binding partner was not identified (Bailly et al, 1992;Pagano et al, 1992;den Elzen and Pines, 2001). Mild permeabilization of cells prior to fixing to remove cytoplasmic cyclin A revealed that the cyclin A co-localized with the g-tubulin stained centrosomes (Figure 5a).…”

Section: Resultsmentioning

confidence: 99%

“…Cyclin A/cdk2 appears to be involved in the activation (Furuno et al, 1999;Mitra and Enders, 2004), and possibly the stabilization of cyclin B, the latter by indirectly inhibiting the anaphase-promoting complex/cyclosome (APC/C) (Lukas et al, 1999). Cyclin A is itself destroyed by the APC/C at prometaphase (den Elzen and Pines, 2001) inferring that its activity is required until that time. In vitro studies using Xenopus extracts have demonstrated that cyclin A/cdk is capable of increasing microtubule nucleation at the centrosomes (Buendia et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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Cyclin A/cdk2 coordinates centrosomal and nuclear mitotic events

et al. 2008

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Cyclin A/cdk2 has a role in progression through S phase, and a large pool is also activated in G 2 phase. Here we report that this G 2 phase pool regulates the timing of progression into mitosis. Knock down of cyclin A by siRNA or addition of a specific cdk2 small molecule inhibitor delayed entry into mitosis by delaying cells in G 2 phase. The G 2 phase-delayed cells contained elevated levels of inactive cyclin B/cdk1. However, increased microtubule nucleation at the centrosomes was observed, and the centrosomes stained for markers of cyclin B/cdk1 activity. Both microtubule nucleation at the centrosomes and the phosphoprotein markers were lost with short-term treatment of the cdk1/2 inhibitor roscovitine but not the Mek1/2 inhibitor U0126. Cyclin A/cdk2 localized at the centrosomes in late G 2 phase after separation of the centrosomes but before the start of prophase. Thus G 2 phase cyclin A/cdk2 controls the timing of entry into mitosis by controlling the subsequent activation of cyclin B/cdk1, but also has an unexpected role in coordinating the activation of cyclin B/cdk1 at the centrosome and in the nucleus.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cyclin A/cdk2 coordinates centrosomal and nuclear mitotic events

et al. 2008

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“…In normal, as well as transformed, human cells, cyclin A becomes detectable at the onset of the S-phase, accumulates throughout S-and G 2 -phase, and then rapidly declines in early mitosis (reviewed in Gillett and Barnes, 13 den Elzen and Pines 15 and Geley et al 16 ). Cyclin A can, therefore, be regarded as a marker of proliferation, since only cells in S-and G 2 -phase or early mitosis stain positively with anticyclin A antibodies, while cells in G 1 -phase remain negative.…”

Section: Discussionmentioning

confidence: 99%

“…Cyclin A levels and associated cyclin-dependent kinase 2 activity steadily increase during S-phase until prometaphase, when cyclin A becomes an unstable protein. 15,16 Cyclin A can, therefore, be regarded as a marker for cells in S-or G 2 -phase of the cell cycle. Similarly, PCNA is extensively used (together with Ki-67) as a marker for cells in S-or G 2 -phase of the cell division cycle.…”

mentioning

confidence: 99%

Aberrant expression of cell cycle regulators in Hodgkin and Reed–Sternberg cells of classical Hodgkin's lymphoma

et al. 2005

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The characteristic Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma, although highly positive for proliferation markers, do not accumulate to excessive cell numbers. These cells are characterized by abortive mitotic cycles, leading to multinucleation or cell death in mitosis. We have previously described high expression of G 1 -phase cyclins in classical Hodgkin's lymphoma, which could explain the high percentage of cells staining for proliferation markers. To further our understanding of proliferation control in classical Hodgkin's lymphoma, we extended our immunohistochemical analysis to the main S-phase cyclin, cyclin A, and its regulators p21 CIP1 and p27 KIP1 . Expression of proliferating cell nuclear antigen (PCNA) was used as an additional marker for cells being in either S-or G 2 -phase. In 47% (112/239) of classical Hodgkin's lymphoma cases p21 CIP1 was detected within a mean frequency of 15% positive Hodgkin's and Reed-Sternberg cells per case. Similarly, 47% (116/249) of the cases stained positively for p27 KIP1 with a mean frequency of expression in Hodgkin's and Reed-Sternberg cells of 12%. In contrast, 90% of the cells in all 246 evaluable classical Hodgkin's lymphoma cases were positive for PCNA. In addition, 98% of Hodgkin's and Reed-Sternberg cells in 99% (250/253) of the cases stained strongly positive for cyclin A. These findings further corroborate the hypothesis that Hodgkin and Reed-Sternberg cells exhibit a disturbed cell cycle with an abnormally short or even absent G 1 -phase. In contrast to other tumors, expression of PCNA or cyclin A had no prognostic value for patient survival.

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“…The order of APC directed substrate degradation is illustrated in figure 1.4. Firstly, APC/Cdc20 targets Cyclin A in prometaphase, Cyclin A destruction is thought to be a required step in the onset of anaphase (Geley et al, 2001;Sigrist et al, 1995;den Elzen and Pines, 2001). …”

Section: Figure 13 Cdk1 Activation Pathwaymentioning

confidence: 99%

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

Smith¹,

Dejsuphong

Balestrini³

et al. 2009

Nat Cell Biol

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The effects of ATM and ATR signalling induced by chromosomal breakage have been described extensively in modulating cell cycle progression up to the onset of mitosis.However, DNA damage checkpoint responses in mitotic cells are not well understood.This thesis reports on the effects of double strand breaks on the progression of mitosis.We found ATM and ATR activation can occur in mitotic Xenopus laevis egg extract and the induction of ATM and ATR by chromosomal breakages inhibits spindle assembly in both Xenopus egg extract and somatic cells. The delay in mitotic progression induced by ATM and ATR was found not to involve major spindle assembly factors activities such as, Cdk1, Plx1 and RCC1/Ran-GTP. However, normal anastral spindles formation around linear DNA coated beads, which can activate ATM and ATR, linked centrosome-driven spindle assembly to ATM and ATR dependent spindle defects. cDNA expression library screening was undertaken to identify novel ATM and ATR targets in this mitotic checkpoint pathway, through which the novel centrosomal protein XCEP63 was identified as a likely candidate. Data obtained from depletion and reconstitution of XCEP63 in Xenopus egg extract established that normal centrosome-driven spindle assembly requires XCEP63. Moreover, ATM and ATR phosphorylates XCEP63 on serine 560 and promotes delocalisation from the centrosome. ATM and ATR inhibition or addition of non-phosphorylable XCEP63 recombinant protein mutated at serine 560 prevents spindle assembly abnormalities.These findings suggest that ATM and ATR regulate mitotic events by targeting XCEP63 and centrosome-dependent spindle assembly. This pathway may provide support for DNA repair processes or regulate cell survival in the presence of mitotic DNA damage. 3

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Cyclin a Is Destroyed in Prometaphase and Can Delay Chromosome Alignment and Anaphase

Cited by 344 publications

References 63 publications

Cyclin A/cdk2 coordinates centrosomal and nuclear mitotic events

Cyclin A/cdk2 coordinates centrosomal and nuclear mitotic events

Aberrant expression of cell cycle regulators in Hodgkin and Reed–Sternberg cells of classical Hodgkin's lymphoma

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

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