Genetic analyses using a mouse cell cycle mutant identifies magoh as a novel gene involved in 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.

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Nucleocytoplasmic Trafficking of G2/M Regulators in Yeast

Molecular Biology of the Cell ◽

10.1091/mbc.e08-03-0286 ◽

2008 ◽

Vol 19 (9) ◽

pp. 4006-4018 ◽

Cited By ~ 25

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.

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The TPX-Like protein TPXL3, but not TPX2, is the primary activator of α Aurora kinases and is essential for embryogenesis in Arabidopsis

10.1101/431791 ◽

2018 ◽

Author(s):

Joanna Boruc ◽

Xingguang Deng ◽

Evelien Mylle ◽

Nienke Besbrugge ◽

Matthias Van Durme ◽

...

Keyword(s):

Cell Cycle ◽

Embryo Development ◽

Specific Interaction ◽

Lower Degree ◽

Genetic Analyses ◽

Aurora Kinases ◽

Functional Specification ◽

Interaction Partners ◽

Cycle Dependent

AbstractAurora kinases are key regulators of mitosis. Multicellular eukaryotes generally possess two functionally diverged types. In plants like Arabidopsis, these are termed α versus β Auroras. As the functional specification of Aurora kinases is determined by their specific interaction partners, we initiated interactomics analyses using both α Aurora kinases (AUR1 and AUR2). Proteomics results revealed the TPX2-Like proteins 2 and 3 (TPXL2/3) prominently associating with α Auroras, as did the conserved TPX2 to a lower degree. Like TPX2, TPXL2 and TPXL3 strongly activated AUR1 kinase but exhibited cell cycle-dependent localization differences on microtubule arrays. The separate functions of TPX2 and TPXL2/3 were also suggested by their different influences on AUR1 localization upon ectopic expressions. Furthermore, genetic analyses disclosed that TPXL3, but not TPX2 and TPXL2, acts non-redundantly to secure proper embryo development. In contrast to vertebrates, plants expanded the TPX2 family for both redundant and unique functions among its members.

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