scholarly journals An RB insensitive to CDK regulation

2016 ◽  
Vol 4 (1) ◽  
pp. e1268242 ◽  
Author(s):  
Manel Joaquin ◽  
Eulàlia de Nadal ◽  
Francesc Posas
Keyword(s):  
Cdk Regulation

scholarly journals Interchangeable Roles for E2F Transcriptional Repression by the Retinoblastoma Protein and p27KIP1–Cyclin-Dependent Kinase Regulation in Cell Cycle Control and Tumor Suppression

2016 ◽  
Vol 37 (2) ◽  
Author(s):  
Michael J. Thwaites ◽  
Matthew J. Cecchini ◽  
Daniel T. Passos ◽  
Ian Welch ◽  
Frederick A. Dick
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Transcriptional Repression ◽  
Cell Cycle Control ◽  
Retinoblastoma Protein ◽  
Level Control ◽  
Mutant Genotype ◽  
Single Mutant ◽  
Cdk Regulation

ABSTRACT The mammalian G1-S phase transition is controlled by the opposing forces of cyclin-dependent kinases (CDK) and the retinoblastoma protein (pRB). Here, we present evidence for systems-level control of cell cycle arrest by pRB-E2F and p27-CDK regulation. By introducing a point mutant allele of pRB that is defective for E2F repression (Rb1 G ) into a p27KIP1 null background (Cdkn1b −/−), both E2F transcriptional repression and CDK regulation are compromised. These double-mutant Rb1 G/G ; Cdkn1b −/− mice are viable and phenocopy Rb1 +/− mice in developing pituitary adenocarcinomas, even though neither single mutant strain is cancer prone. Combined loss of pRB-E2F transcriptional regulation and p27KIP1 leads to defective proliferative control in response to various types of DNA damage. In addition, Rb1 G/G ; Cdkn1b −/− fibroblasts immortalize faster in culture and more frequently than either single mutant genotype. Importantly, the synthetic DNA damage arrest defect caused by Rb1 G/G ; Cdkn1b −/− mutations is evident in the developing intermediate pituitary lobe where tumors ultimately arise. Our work identifies a unique relationship between pRB-E2F and p27-CDK control and offers in vivo evidence that pRB is capable of cell cycle control through E2F-independent effects.

scholarly journals Nucleocytoplasmic Trafficking of G2/M Regulators in Yeast

2008 ◽  
Vol 19 (9) ◽  
pp. 4006-4018 ◽  
Author(s):  
Mignon A. Keaton ◽  
Lee Szkotnicki ◽  
Aron R. Marquitz ◽  
Jake Harrison ◽  
Trevin R. Zyla ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Nuclear Import ◽  
Nuclear Export ◽  
Cell Cycle Regulators ◽  
Cyclin Dependent Kinase ◽  
Nucleocytoplasmic Trafficking ◽  
Nucleocytoplasmic Shuttling ◽  
Upstream Regulator ◽  
Cellular Compartments ◽  
Cdk Regulation

Nucleocytoplasmic shuttling is prevalent among many cell cycle regulators controlling the G2/M transition. Shuttling of cyclin/cyclin-dependent kinase (CDK) complexes is thought to provide access to substrates stably located in either compartment. Because cyclin/CDK shuttles between cellular compartments, an upstream regulator that is fixed in one compartment could in principle affect the entire cyclin/CDK pool. Alternatively, the regulators themselves may need to shuttle to effectively regulate their moving target. Here, we identify localization motifs in the budding yeast Swe1p (Wee1) and Mih1p (Cdc25) cell cycle regulators. Replacement of endogenous Swe1p or Mih1p with mutants impaired in nuclear import or export revealed that the nuclear pools of Swe1p and Mih1p were more effective in CDK regulation than were the cytoplasmic pools. Nevertheless, shuttling of cyclin/CDK complexes was sufficiently rapid to coordinate nuclear and cytoplasmic events even when Swe1p or Mih1p were restricted to one compartment. Additionally, we found that Swe1p nuclear export was important for its degradation. Because Swe1p degradation is regulated by cytoskeletal stress, shuttling of Swe1p between nucleus and cytoplasm serves to couple cytoplasmic stress to nuclear cyclin/CDK inhibition.

scholarly journals Structures of P. falciparum PfPK5 Test the CDK Regulation Paradigm and Suggest Mechanisms of Small Molecule Inhibition

Structure ◽  
2003 ◽  
Vol 11 (11) ◽  
pp. 1329-1337 ◽  
Author(s):  
Simon Holton ◽  
Anais Merckx ◽  
Darren Burgess ◽  
Christian Doerig ◽  
Martin Noble ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibition ◽  
Cdk Regulation

scholarly journals Genetic analyses using a mouse cell cycle mutant identifies magoh as a novel gene involved in Cdk regulation

2011 ◽  
Vol 16 (2) ◽  
pp. 166-178 ◽  
Author(s):  
Makoto Inaki ◽  
Dai Kato ◽  
Takahiko Utsugi ◽  
Fumitoshi Onoda ◽  
Fumio Hanaoka ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mouse Cell ◽  
Genetic Analyses ◽  
Novel Gene ◽  
Cdk Regulation

scholarly journals The origin of CDK regulation

2001 ◽  
Vol 3 (8) ◽  
pp. E182-E184 ◽  
Author(s):  
Anatoliy Li ◽  
J. Julian Blow
Keyword(s):  
Cdk Regulation

scholarly journals CDK Regulation of Meiosis: Lessons from S. cerevisiae and S. pombe

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 723
Author(s):  
Anne M. MacKenzie ◽  
Soni Lacefield
Keyword(s):  
Fission Yeast ◽  
Yeast Species ◽  
Regulatory System ◽  
Cyclin Dependent Kinase ◽  
Post Translational Modifications ◽  
Regulatory Subunits ◽  
Meiotic Progression ◽  
The Past ◽  
Cdk Regulation

Meiotic progression requires precise orchestration, such that one round of DNA replication is followed by two meiotic divisions. The order and timing of meiotic events is controlled through the modulation of the phosphorylation state of proteins. Key components of this phospho-regulatory system include cyclin-dependent kinase (CDK) and its cyclin regulatory subunits. Over the past two decades, studies in budding and fission yeast have greatly informed our understanding of the role of CDK in meiotic regulation. In this review, we provide an overview of how CDK controls meiotic events in both budding and fission yeast. We discuss mechanisms of CDK regulation through post-translational modifications and changes in the levels of cyclins. Finally, we highlight the similarities and differences in CDK regulation between the two yeast species. Since CDK and many meiotic regulators are highly conserved, the findings in budding and fission yeasts have revealed conserved mechanisms of meiotic regulation among eukaryotes.

scholarly journals CDK Phosphorylation of a Novel NLS-NES Module Distributed between Two Subunits of the Mcm2-7 Complex Prevents Chromosomal Rereplication

2005 ◽  
Vol 16 (10) ◽  
pp. 5026-5039 ◽  
Author(s):  
Muluye E. Liku ◽  
Van Q. Nguyen ◽  
Audrey W. Rosales ◽  
Kaoru Irie ◽  
Joachim J. Li
Keyword(s):  
Nuclear Localization ◽  
Nuclear Export ◽  
Protein Localization ◽  
Nuclear Export Signal ◽  
Replication Initiation ◽  
Nuclear Localization Signals ◽  
Cdk Phosphorylation ◽  
In Cis ◽  
Net Export ◽  
Cdk Regulation

Cyclin-dependent kinases (CDKs) use multiple mechanisms to block reassembly of prereplicative complexes (pre-RCs) at replication origins to prevent inappropriate rereplication. In Saccharomyces cerevisiae, one of these mechanisms promotes the net nuclear export of a pre-RC component, the Mcm2-7 complex, during S, G2, and M phases. Here we identify two partial nuclear localization signals (NLSs) on Mcm2 and Mcm3 that are each necessary, but not sufficient, for nuclear localization of the Mcm2-7 complex. When brought together in cis, however, the two partial signals constitute a potent NLS, sufficient for robust nuclear localization when fused to an otherwise cytoplasmic protein. We also identify a Crm1-dependent nuclear export signal (NES) adjacent to the Mcm3 NLS. Remarkably, the Mcm2-Mcm3 NLS and the Mcm3 NES are sufficient to form a transport module that recapitulates the cell cycle-regulated localization of the entire Mcm2-7 complex. Moreover, we show that CDK regulation promotes net export by phosphorylation of the Mcm3 portion of this module and that nuclear export of the Mcm2-7 complex is sufficient to disrupt replication initiation. We speculate that the distribution of partial transport signals among distinct subunits of a complex may enhance the specificity of protein localization and raises the possibility that previously undetected distributed transport signals are used by other multiprotein complexes.

scholarly journals Cyclin E Associates with Components of the Pre-mRNA Splicing Machinery in Mammalian Cells

1998 ◽  
Vol 18 (8) ◽  
pp. 4526-4536 ◽  
Author(s):  
Wolfgang Seghezzi ◽  
Katrin Chua ◽  
Frances Shanahan ◽  
Or Gozani ◽  
Robin Reed ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
Specific Inhibitor ◽  
Mrna Splicing ◽  
Core Proteins ◽  
Associated Proteins ◽  
Cdk Regulation

ABSTRACT Cyclin E-cdk2 is a critical regulator of cell cycle progression from G1 into S phase in mammalian cells. Despite this important function little is known about the downstream targets of this cyclin-kinase complex. Here we have identified components of the pre-mRNA processing machinery as potential targets of cyclin E-cdk2. Cyclin E-specific antibodies coprecipitated a number of cyclin E-associated proteins from cell lysates, among which are the spliceosome-associated proteins, SAP 114, SAP 145, and SAP 155, as well as the snRNP core proteins B′ and B. The three SAPs are all subunits of the essential splicing factor SF3, a component of U2 snRNP. Cyclin E antibodies also specifically immunoprecipitated U2 snRNA and the spliceosome from splicing extracts. We demonstrate that SAP 155 serves as a substrate for cyclin E-cdk2 in vitro and that its phosphorylation in the cyclin E complex can be inhibited by the cdk-specific inhibitor p21. SAP 155 contains numerous cdk consensus phosphorylation sites in its N terminus and is phosphorylated prior to catalytic step II of the splicing pathway, suggesting a potential role for cdk regulation. These findings provide evidence that pre-mRNA splicing may be linked to the cell cycle machinery in mammalian cells.

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