Role of Cdc6 During Oogenesis and Early Embryo Development in Mouse and Xenopus laevis

Borsuk, Ewa; Jachowicz, Joanna W.; Kloc, Małgorzata; Tassan, Jean Pierre; Kubiak, Jacek Z.

doi:10.1007/978-3-319-44820-6_7

Cited by 5 publications

(8 citation statements)

References 31 publications

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“…In addition to its role in mitotic exit in yeast and human cells [ 90 , 95 , 96 ], our group has also showed the role of CDC6 in delaying mitotic entry by inhibiting CDK1 activity in Xenopus laevis premitotic cell-free extracts [ 9 , 10 , 11 , 12 , 13 , 14 ]. CDC6 associated with CDK1 during the M-phase rapidly dissociates from this kinase immediately after CDK1 inactivation, suggesting that once CDK1 is fully inactivated by separation from cyclin B, the association with CDC6 becomes unnecessary.…”

Section: Cdc6 As An Upstream Regulator Of Cdk1 Through Its Inhibitionmentioning

confidence: 99%

“…The important hint to the role of CDC6 in CDK1 activation process was its abovementioned function in the M-phase exit described in yeast and human cells. Through biochemical analysis of Xenopus embryo cell-free extracts we showed that a recombinant CDC6 protein acts as an inhibitor of CDK1 during the first embryonic mitosis in Xenopus leavis [ 9 , 10 , 11 , 12 , 13 , 14 ]. Importantly, when endogenous CDC6 is depleted, the first, initial and slow phase of CDK1 activation is removed, and the kinase activation ceases to be biphasic.…”

Section: Cdc6 As An Upstream Regulator Of Cdk1 Through Its Inhibitionmentioning

confidence: 99%

“…Importantly, when endogenous CDC6 is depleted, the first, initial and slow phase of CDK1 activation is removed, and the kinase activation ceases to be biphasic. This, in turn, accelerates the timing of mitosis and the pic of CDK1 activity induced by the CDC25/CDK1 activation loop [ 9 , 10 , 11 , 12 , 13 , 14 ]. Adding a recombinant CDC6 completely reverses all these effects [ 14 , 16 , 95 ].…”

Section: Cdc6 As An Upstream Regulator Of Cdk1 Through Its Inhibitionmentioning

confidence: 99%

“…This, in turn, accelerates the timing of mitosis and the pic of CDK1 activity induced by the CDC25/CDK1 activation loop [ 9 , 10 , 11 , 12 , 13 , 14 ]. Adding a recombinant CDC6 completely reverses all these effects [ 14 , 16 , 95 ]. Additionally, exogenous cyclin A or cyclin B added to Xenopus laevis cycling extracts leads to distinct regulation of the kinetics of this mitotic kinase activity [ 9 ].…”

Section: Cdc6 As An Upstream Regulator Of Cdk1 Through Its Inhibitionmentioning

confidence: 99%

“…Surprisingly for us, we found a CDC6 protein associated with the active mitotic CDK. CDC6 inhibits CDK1 throughout the whole period of the M-phase (including the highest peak of CDK1 activity just prior its inactivation) [ 9 , 10 , 11 , 12 , 13 , 14 ]. CDC6 is an evolutionarily conserved member of the AAA + ATPase family and was only known as the S-phase activator [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

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CDC6 as a Key Inhibitory Regulator of CDK1 Activation Dynamics and the Timing of Mitotic Entry and Progression

Dika

Dudka

Kloc

et al. 2023

Biology

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Timely mitosis is critically important for early embryo development. It is regulated by the activity of the conserved protein kinase CDK1. The dynamics of CDK1 activation must be precisely controlled to assure physiologic and timely entry into mitosis. Recently, a known S-phase regulator CDC6 emerged as a key player in mitotic CDK1 activation cascade in early embryonic divisions, operating together with Xic1 as a CDK1 inhibitor upstream of the Aurora A and PLK1, both CDK1 activators. Herein, we review the molecular mechanisms that underlie the control of mitotic timing, with special emphasis on how CDC6/Xic1 function impacts CDK1 regulatory network in the Xenopus system. We focus on the presence of two independent mechanisms inhibiting the dynamics of CDK1 activation, namely Wee1/Myt1- and CDC6/Xic1-dependent, and how they cooperate with CDK1-activating mechanisms. As a result, we propose a comprehensive model integrating CDC6/Xic1-dependent inhibition into the CDK1-activation cascade. The physiological dynamics of CDK1 activation appear to be controlled by the system of multiple inhibitors and activators, and their integrated modulation ensures concomitantly both the robustness and certain flexibility of the control of this process. Identification of multiple activators and inhibitors of CDK1 upon M-phase entry allows for a better understanding of why cells divide at a specific time and how the pathways involved in the timely regulation of cell division are all integrated to precisely tune the control of mitotic events.

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Section: Cdc6 As An Upstream Regulator Of Cdk1 Through Its Inhibitionmentioning

confidence: 99%

Section: Cdc6 As An Upstream Regulator Of Cdk1 Through Its Inhibitionmentioning

confidence: 99%

Section: Cdc6 As An Upstream Regulator Of Cdk1 Through Its Inhibitionmentioning

confidence: 99%

Section: Cdc6 As An Upstream Regulator Of Cdk1 Through Its Inhibitionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CDC6 as a Key Inhibitory Regulator of CDK1 Activation Dynamics and the Timing of Mitotic Entry and Progression

Dika

Dudka

Kloc

et al. 2023

Biology

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Phosphorylation Dynamics Dominate the Regulated Proteome during Early Xenopus Development

Peuchen

Cox

Sun

et al. 2017

Sci Rep

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The earliest stages of animal development are largely controlled by changes in protein phosphorylation mediated by signaling pathways and cyclin-dependent kinases. In order to decipher these complex networks and to discover new aspects of regulation by this post-translational modification, we undertook an analysis of the X. laevis phosphoproteome at seven developmental stages beginning with stage VI oocytes and ending with two-cell embryos. Concurrent measurement of the proteome and phosphoproteome enabled measurement of phosphosite occupancy as a function of developmental stage. We observed little change in protein expression levels during this period. We detected the expected phosphorylation of MAP kinases, translational regulatory proteins, and subunits of APC/C that validate the accuracy of our measurements. We find that more than half the identified proteins possess multiple sites of phosphorylation that are often clustered, where kinases work together in a hierarchical manner to create stretches of phosphorylated residues, which may be a means to amplify signals or stabilize a particular protein conformation. Conversely, other proteins have opposing sites of phosphorylation that seemingly reflect distinct changes in activity during this developmental timeline.

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CDC6 regulates mitotic CDK1 via cyclin B and not cyclin A and acts through abona fideCDK inhibitor Xic1

Wechselberger

Djeghout

et al. 2020

Preprint

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The timing of the M-phase entry and its progression are precisely controlled by a CDC6dependent mechanism that inhibits the major mitotic kinase CDK1, and, thus, regulates the dynamic of CDK1 during the M-phase. In this paper, we describe the differential regulation of the mitotic CDK1 dynamics by exogenous cyclin A or a non-degradable cyclin B added to the Xenopus laevis embryo cycling extracts. We showed that the variations in the level of cyclin B modify both CDK1 activity and the timing of the M-phase progression, while the cyclin A levels modify only CDK1 activity without changing the timing of the M-phase events. In consequence, CDC6 regulates the M-phase through endogenous cyclin B, but not cyclin A, which we demonstrated directly by the depletion of cyclin A, and the addition of CDC6 to the cycling extracts. Further, we showed, by p9 precipitation (p9 protein associates with Cyclin-Dependent Kinases, CDK), followed by the Western blotting that CDC6, and the bona fide CDK1 inhibitor Xic1, associate with CDK1 and/or another CDK present in Xenopus embryos, the CDK2.Finally, we demonstrated that the Xic1 temoprarily separates from the mitotic CDK complexes during the peak of CDK1 activity. These data show the differential coordination of the M-phase progression by CDK1/cyclin A and CDK1/cyclin B, confirm the critical role of the CDC6dependent CDK1 inhibition in this process and show that CDC6 acts through the cyclin B-and not cyclin A/CDK complexes. This CDC6-and cyclin B-dependent mechanism may also depend on the precisely regulated association of Xic1 with the CDK complexes. We postulate that the dissociation of Xic1 from the CDK complexes allows the maximal activation of CDK1 during the M-phase.

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Role of Cdc6 During Oogenesis and Early Embryo Development in Mouse and Xenopus laevis

Cited by 5 publications

References 31 publications

CDC6 as a Key Inhibitory Regulator of CDK1 Activation Dynamics and the Timing of Mitotic Entry and Progression

CDC6 as a Key Inhibitory Regulator of CDK1 Activation Dynamics and the Timing of Mitotic Entry and Progression

Phosphorylation Dynamics Dominate the Regulated Proteome during Early Xenopus Development

CDC6 regulates mitotic CDK1 via cyclin B and not cyclin A and acts through abona fideCDK inhibitor Xic1

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