scholarly journals CDKD-dependent activation of CDKA;1 controls microtubule dynamics and cytokinesis during meiosis

2020 ◽  
Vol 219 (8) ◽  
Author(s):  
Kostika Sofroni ◽  
Hirotomo Takatsuka ◽  
Chao Yang ◽  
Nico Dissmeyer ◽  
Shinichiro Komaki ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Kinase Activity ◽  
Nuclear Division ◽  
Cyclin Dependent Kinase ◽  
Loss Of Function ◽  
Precise Control ◽  
Fine Grained ◽  
Cytoskeleton Dynamics ◽  
Cell Cycle Regulator Cyclin ◽  
Cell Cycle Kinase

Precise control of cytoskeleton dynamics and its tight coordination with chromosomal events are key to cell division. This is exemplified by formation of the spindle and execution of cytokinesis after nuclear division. Here, we reveal that the central cell cycle regulator CYCLIN DEPENDENT KINASE A;1 (CDKA;1), the Arabidopsis homologue of Cdk1 and Cdk2, partially in conjunction with CYCLIN B3;1 (CYCB3;1), is a key regulator of the microtubule cytoskeleton in meiosis. For full CDKA;1 activity, the function of three redundantly acting CDK-activating kinases (CAKs), CDKD;1, CDKD;2, and CDKD;3, is necessary. Progressive loss of these genes in combination with a weak loss-of-function mutant in CDKA;1 allowed a fine-grained dissection of the requirement of cell-cycle kinase activity for meiosis. Notably, a moderate reduction of CDKA;1 activity converts the simultaneous cytokinesis in Arabidopsis, i.e., one cytokinesis separating all four meiotic products concurrently into two successive cytokineses with cell wall formation after the first and second meiotic division, as found in many monocotyledonous species.

scholarly journals Ras controls growth, survival and differentiation in the Drosophila eye by different thresholds of MAP kinase activity

Development ◽  
2001 ◽  
Vol 128 (9) ◽  
pp. 1687-1696 ◽  
Author(s):  
K. Halfar ◽  
C. Rommel ◽  
H. Stocker ◽  
E. Hafen
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Photoreceptor Cells ◽  
Loss Of Function ◽  
Cellular Functions ◽  
Partial Loss ◽  
Cycle Progression ◽  
Mapk Activity ◽  
Dividing Cells

Ras mediates a plethora of cellular functions during development. In the developing eye of Drosophila, Ras performs three temporally separate functions. In dividing cells, it is required for growth but is not essential for cell cycle progression. In postmitotic cells, it promotes survival and subsequent differentiation of ommatidial cells. In the present paper, we have analyzed the different roles of Ras during eye development by using molecularly defined complete and partial loss-of-function mutations of Ras. We show that the three different functions of Ras are mediated by distinct thresholds of MAPK activity. Low MAPK activity prolongs cell survival and permits differentiation of R8 photoreceptor cells while high or persistent MAPK activity is sufficient to precociously induce R1-R7 photoreceptor differentiation in dividing cells.

scholarly journals BRCA1 Is Phosphorylated at Serine 1497 In Vivo at a Cyclin-Dependent Kinase 2 Phosphorylation Site

1999 ◽  
Vol 19 (7) ◽  
pp. 4843-4854 ◽  
Author(s):  
Heinz Ruffner ◽  
Wei Jiang ◽  
A. Grey Craig ◽  
Tony Hunter ◽  
Inder M. Verma
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Phosphorylation Site ◽  
Cyclin A ◽  
Dominant Negative ◽  
Protein Kinase Activity ◽  
Cyclin Dependent Kinase

ABSTRACT BRCA1 is a cell cycle-regulated nuclear protein that is phosphorylated mainly on serine and to a lesser extent on threonine residues. Changes in phosphorylation occur in response to cell cycle progression and DNA damage. Specifically, BRCA1 undergoes hyperphosphorylation during late G1 and S phases of the cell cycle. Here we report that BRCA1 is phosphorylated in vivo at serine 1497 (S1497), which is part of a cyclin-dependent kinase (CDK) consensus site. S1497 can be phosphorylated in vitro by CDK2-cyclin A or E. BRCA1 coimmunoprecipitates with an endogenous serine-threonine protein kinase activity that phosphorylates S1497 in vitro. This cellular kinase activity is sensitive to transfection of a dominant negative form of CDK2 as well as the application of the CDK inhibitors p21 and butyrolactone I but not p16. Furthermore, BRCA1 coimmunoprecipitates with CDK2 and cyclin A. These results suggest that the endogenous kinase activity is composed of CDK2-cyclin complexes, at least in part, concordant with the G1/S-specific increase in BRCA1 phosphorylation.

scholarly journals The accumulation of an E2F-p130 transcriptional repressor distinguishes a G0 cell state from a G1 cell state.

1996 ◽  
Vol 16 (12) ◽  
pp. 6965-6976 ◽  
Author(s):  
E J Smith ◽  
G Leone ◽  
J DeGregori ◽  
L Jakoi ◽  
J R Nevins
Keyword(s):  
Cell Cycle ◽  
Target Genes ◽  
Kinase Activity ◽  
Transcriptional Repressor ◽  
Negative Control ◽  
Cyclin Dependent Kinase ◽  
Cell State ◽  
Quiescent Cells ◽  
Cycle Dependent ◽  
E2f Proteins

Previous studies have demonstrated cell cycle-dependent specificities in the interactions of E2F proteins with Rb family members. We now show that the formation of an E2F-p130 complex is unique to cells in a quiescent, G0 state. The E2F-p130 complex does not reform when cells reenter a proliferative state and cycle through G1. The presence of an E2F-p130 complex in quiescent cells coincides with the E2F-mediated repression of transcription of the E2F1 gene, and we show that the E2F sites in the E2F1 promoter are important as cells enter quiescence but play no apparent role in cycling cells. In addition, the decay of the E2F-p130 complex as cells reenter the cell cycle requires the action of G1 cyclin-dependent kinase activity. We conclude that the accumulation of the E2F-p130 complex in quiescent cells provides a negative control of certain key target genes and defines a functional distinction between these G0 cells and cells that exist transiently in G1.

scholarly journals p27Kip1 Inhibits Cyclin D-Cyclin-Dependent Kinase 4 by Two Independent Modes

2008 ◽  
Vol 29 (4) ◽  
pp. 986-999 ◽  
Author(s):  
Arpita Ray ◽  
Melissa K. James ◽  
Stéphane Larochelle ◽  
Robert P. Fisher ◽  
Stacy W. Blain
Keyword(s):  
Cell Cycle ◽  
Active Site ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Growth Conditions ◽  
Cyclin D ◽  
Cyclin Dependent Kinase ◽  
Proliferating Cells ◽  
Cell Cycle Reentry

ABSTRACT Cell cycle progression is regulated by cyclin-dependent kinases (cdk's), which in turn are regulated by their interactions with stoichiometric inhibitors, such as p27Kip1. Although p27 associates with cyclin D-cyclin-dependent kinase 4 (cdk4) constitutively, whether or not it inhibits this complex is dependent on the absence or presence of a specific tyrosine phosphorylation that converts p27 from a bound inhibitor to a bound noninhibitor under different growth conditions. This phosphorylation occurs within the 3-10 helix of p27 and may dislodge the helix from cdk4's active site to allow ATP binding. Here we show that the interaction of nonphosphorylated p27 with cdk4 also prevents the activating phosphorylation of the T-loop by cyclin H-cdk7, the cdk-activating kinase (CAK). Even though the cyclin H-cdk7 complex is present and active in contact-arrested cells, p27's association with cyclin D-cdk4 prevents T-loop phosphorylation. When p27 is tyrosine phosphorylated in proliferating cells or in vitro with the tyrosine Y kinase Abl, phosphorylation of cdk4 by cyclin H-cdk7 is permitted, even without dissociation of p27. This suggests that upon release from the contact-arrested state, a temporal order for the reactivation of inactive p27-cyclin D-cdk4 complexes must exist: p27 must be Y phosphorylated first, directly permitting cyclin H-cdk7 phosphorylation of residue T172 and the consequent restoration of kinase activity. The non-Y-phosphorylated p27-cyclin D-cdk4 complex could be phosphorylated by purified Csk1, a single-subunit CAK from fission yeast, but was still inactive due to p27's occlusion of the active site. Thus, the two modes by which p27 inhibits cyclin D-cdk4 are independent and may reinforce one another to inhibit kinase activity in contact-arrested cells, while maintaining a reservoir of preformed complex that can be activated rapidly upon cell cycle reentry.

scholarly journals Cdc28 Activates Exit from Mitosis in Budding Yeast

2000 ◽  
Vol 149 (7) ◽  
pp. 1361-1376 ◽  
Author(s):  
Adam D. Rudner ◽  
Kevin G. Hardwick ◽  
Andrew W. Murray
Keyword(s):  
Cell Cycle ◽  
Kinase Activity ◽  
Budding Yeast ◽  
G1 Phase ◽  
Phosphorylation Sites ◽  
Cyclin Dependent Kinase ◽  
Anaphase Promoting Complex ◽  
Reduced Activity

The activity of the cyclin-dependent kinase 1 (Cdk1), Cdc28, inhibits the transition from anaphase to G1 in budding yeast. CDC28-T18V, Y19F (CDC28-VF), a mutant that lacks inhibitory phosphorylation sites, delays the exit from mitosis and is hypersensitive to perturbations that arrest cells in mitosis. Surprisingly, this behavior is not due to a lack of inhibitory phosphorylation or increased kinase activity, but reflects reduced activity of the anaphase-promoting complex (APC), a defect shared with other mutants that lower Cdc28/Clb activity in mitosis. CDC28-VF has reduced Cdc20- dependent APC activity in mitosis, but normal Hct1- dependent APC activity in the G1 phase of the cell cycle. The defect in Cdc20-dependent APC activity in CDC28-VF correlates with reduced association of Cdc20 with the APC. The defects of CDC28-VF suggest that Cdc28 activity is required to induce the metaphase to anaphase transition and initiate the transition from anaphase to G1 in budding yeast.

scholarly journals AP-1 blockade in breast cancer cells causes cell cycle arrest by suppressing G1 cyclin expression and reducing cyclin-dependent kinase activity

Oncogene ◽  
2004 ◽  
Vol 23 (50) ◽  
pp. 8238-8246 ◽  
Author(s):  
Yongmin Liu ◽  
Chunhua Lu ◽  
Qiang Shen ◽  
Debbie Munoz-Medellin ◽  
Heetae Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Kinase Activity ◽  
Cyclin Dependent Kinase ◽  
Cycle Arrest ◽  
G1 Cyclin

KSHV viral cyclin binds to p27KIP1 in primary effusion lymphomas

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3349-3354 ◽  
Author(s):  
Annika Järviluoma ◽  
Sonja Koopal ◽  
Susanna Räsänen ◽  
Tomi P. Mäkelä ◽  
Päivi M. Ojala
Keyword(s):  
Cell Cycle ◽  
Kinase Activity ◽  
Kaposi Sarcoma ◽  
Cyclin Dependent Kinase ◽  
Cell Cycle Inhibitor ◽  
Non Hodgkin Lymphoma ◽  
Viral Cyclin ◽  
Primary Effusion Lymphomas ◽  
Proliferative Signal

Abstract Primary effusion lymphomas (PELs) represent a unique non-Hodgkin lymphoma that is consistently infected by Kaposi sarcoma herpesvirus (KSHV). PEL cells express high levels of the cell cycle inhibitor p27KIP1 and yet proliferate actively. KSHV genome encodes a viral cyclin homolog, v-cyclin, which has previously been implicated in down-regulation of p27KIP1 levels. To address how PEL cells can tolerate high p27KIP1 levels, we investigated functional interactions between v-cyclin and p27KIP1 using PEL-derived cell lines as a model system. Here we demonstrate that v-cyclin and p27KIP1 stably associate in PEL cells in vivo suggesting an attractive model by which p27KIP1 is inactivated in the actively proliferating PEL cells. Moreover, we show that v-cyclin and cyclin-dependent kinase 6 (CDK6) form an active kinase without p27KIP1 and that CDK6 is the in vivo catalytic subunit of v-cyclin in PEL cells. These findings suggest that KSHV may promote oncogenesis in PEL by expressing v-cyclin, which both overrides negative cell cycle controls present in the PEL precursor cells and induces a strong proliferative signal via CDK6 kinase activity. (Blood. 2004;104:3349-3354)

scholarly journals Increased expression of senescence markers in cystic fibrosis airways

2013 ◽  
Vol 304 (6) ◽  
pp. L394-L400 ◽  
Author(s):  
Bernard M. Fischer ◽  
Jessica K. Wong ◽  
Simone Degan ◽  
Apparao B. Kummarapurugu ◽  
Shuo Zheng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cystic Fibrosis ◽  
Cell Cycle Arrest ◽  
Airway Epithelium ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Airway Epithelial Cells ◽  
Cyclin Dependent Kinase ◽  
Control Subjects ◽  
Cycle Arrest

Cystic Fibrosis (CF) is a chronic lung disease characterized by chronic neutrophilic airway inflammation and increased levels of neutrophil elastase (NE) in the airways. We have previously reported that NE treatment triggers cell cycle arrest. Cell cycle arrest can lead to senescence, a complete loss of replicative capacity. Importantly, senescent cells can be proinflammatory and would perpetuate CF chronic inflammation. By immunohistochemistry, we evaluated whether airway sections from CF and control subjects expressed markers of senescence, including p16INK4a(p16), a cyclin-dependent kinase inhibitor, phospho-Histone H2A.X (γH2A.X), and phospho-checkpoint 2 kinase (phospho-Chk2), which are also DNA damage response markers. Compared with airway epithelium from control subjects, CF airway epithelium had increased levels of expression of all three senescence markers. We hypothesized that the high load of NE in the CF airway triggers epithelial senescence by upregulating expression of p16, which inhibits cyclin-dependent kinase 4 (CDK4). Normal human bronchial epithelial (NHBE) cells, cultured in air-liquid interface were treated with NE (0, 200, and 500 nM) to induce visible injury. Total cell lysates were collected and evaluated by Western analysis for p16 protein expression and CDK4 kinase activity. NE significantly increased p16 expression and decreased CDK4 kinase activity in NHBE cells. These results support the concept that NE triggers expression of senescence markers in CF airway epithelial cells.

scholarly journals Requirement of Cyclin E-Cdk2 Inhibition in p16INK4a-Mediated Growth Suppression

1998 ◽  
Vol 18 (9) ◽  
pp. 5284-5290 ◽  
Author(s):  
Hong Jiang ◽  
Hubert S. Chou ◽  
Liang Zhu
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Tumor Cells ◽  
Kinase Activity ◽  
Cyclin E ◽  
Growth Suppression ◽  
Dominant Negative ◽  
Cyclin D ◽  
Loss Of Function

ABSTRACT Loss-of-function mutations of p16 INK4a have been identified in a large number of human tumors. An established biochemical function of p16 is its ability to specifically inhibit cyclin D-dependent kinases in vitro, and this inhibition is believed to be the cause of the p16-mediated G1 cell cycle arrest after reintroduction of p16 into p16-deficient tumor cells. However, a mutant of Cdk4, Cdk4N158, designed to specifically inhibit cyclin D-dependent kinases through dominant negative interference, was unable to arrest the cell cycle of the same cells (S. van den Heuvel and E. Harlow, Science 262:2050–2054, 1993). In this study, we determined functional differences between p16 and Cdk4N158. We show that p16 and Cdk4N158 inhibit the kinase activity of cellular cyclin D1 complexes through different mechanisms. p16 dissociated cyclin D1-Cdk4 complexes with the release of bound p27 KIP1 , while Cdk4N158 formed complexes with cyclin D1 and p27. In cells induced to overexpress p16, a higher portion of cellular p27 formed complexes with cyclin E-Cdk2, and Cdk2-associated kinase activities were correspondingly inhibited. Cells engineered to express moderately elevated levels of cyclin E became resistant to p16-mediated growth suppression. These results demonstrate that inhibition of cyclin D-dependent kinase activity may not be sufficient to cause G1 arrest in actively proliferating tumor cells. Inhibition of cyclin E-dependent kinases is required in p16-mediated growth suppression.

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