scholarly journals Cyclin N-Terminal Domain-Containing-1 Coordinates Meiotic Crossover Formation with Cell-Cycle Progression in a Cyclin-Independent Manner

Cell Reports ◽  
2020 ◽  
Vol 32 (1) ◽  
pp. 107858 ◽  
Author(s):  
Stephen Gray ◽  
Emerson R. Santiago ◽  
Joshua S. Chappie ◽  
Paula E. Cohen
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Independent Manner ◽  
Cycle Progression ◽  
Terminal Domain ◽  
Meiotic Crossover

Pyk2 and FAK differentially regulate progression of the cell cycle

2000 ◽  
Vol 113 (17) ◽  
pp. 3063-3072 ◽  
Author(s):  
J. Zhao ◽  
C. Zheng ◽  
J. Guan
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Cell Cycle Progression ◽  
Expression System ◽  
Chimeric Protein ◽  
Kinase Domain ◽  
Cycle Progression ◽  
Erk Activation ◽  
Terminal Domain ◽  
Cycle Regulation

We have previously identified FAK and its associated signaling pathways as a mediator of cell cycle progression by integrins. In this report, we have analyzed the potential role and mechanism of Pyk2, a tyrosine kinase closely related to FAK, in cell cycle regulation by using tetracycline-regulated expression system as well as chimeric molecules. We have found that induction of Pyk2 inhibited G(1) to S phase transition whereas comparable induction of FAK expression accelerated it. Furthermore, expression of a chimeric protein containing Pyk2 N-terminal and kinase domain and FAK C-terminal domain (PFhy1) increased cell cycle progression as FAK. Conversely, the complementary chimeric molecule containing FAK N-terminal and kinase domain and Pyk2 C-terminal domain (FPhy2) inhibited cell cycle progression to an even greater extent than Pyk2. Biochemical analyses indicated that Pyk2 and FPhy2 stimulated JNK activation whereas FAK or PFhy1 had little effect on it, suggesting that differential activation of JNK by Pyk2 may contribute to its inhibition of cell cycle progression. In addition, Pyk2 and FPhy2 to a greater extent also inhibited Erk activation in cell adhesion whereas FAK and PFhy1 stimulated it, suggesting a role for Erk activation in mediating differential regulation of cell cycle by Pyk2 and FAK. A role for Erk and JNK pathways in mediating the cell cycle regulation by FAK and Pyk2 was also confirmed by using chemical inhibitors for these pathways. Finally, we showed that while FAK and PFhy1 were present in focal contacts, Pyk2 and FPhy2 were localized in the cytoplasm. Interestingly, both Pyk2 and FPhy2 (to a greater extent) were tyrosine phosphorylated and associated with Src and Fyn. This suggested that they may inhibit Erk activation in an analogous manner as the mislocalized FAK mutant (Δ)C14 described previously by competing with endogenous FAK for binding signaling molecules such as Src and Fyn. This model is further supported by an inhibition of endogenous FAK association with active Src by Pyk2 and FPhy2 and a partial rescue by FAK of Pyk2-mediated cell cycle inhibition.

scholarly journals Regulation of CDK7–Carboxyl-Terminal Domain Kinase Activity by the Tumor Suppressor p16INK4A Contributes to Cell Cycle Regulation

2000 ◽  
Vol 20 (20) ◽  
pp. 7726-7734 ◽  
Author(s):  
Eiji Nishiwaki ◽  
Saralinda L. Turner ◽  
Susanna Harju ◽  
Shiro Miyazaki ◽  
Masahide Kashiwagi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Rna Polymerase Ii ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Alternative Pathway ◽  
Cycle Progression ◽  
Terminal Domain ◽  
Carboxyl Terminal Domain ◽  
Carboxyl Terminal

ABSTRACT The eukaryotic cell cycle is regulated by cyclin-dependent kinases (CDKs). CDK4 and CDK6, which are activated by D-type cyclins during the G1 phase of the cell cycle, are thought to be responsible for phosphorylation of the retinoblastoma gene product (pRb). The tumor suppressor p16INK4A inhibits phosphorylation of pRb by CDK4 and CDK6 and can thereby block cell cycle progression at the G1/S boundary. Phosphorylation of the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II by general transcription factor TFIIH is believed to be an important regulatory event in transcription. TFIIH contains a CDK7 kinase subunit and phosphorylates the CTD. We have previously shown that p16INK4A inhibits phosphorylation of the CTD by TFIIH. Here we report that the ability of p16INK4A to inhibit CDK7-CTD kinase contributes to the capacity to induce cell cycle arrest. These results suggest that p16INK4A may regulate cell cycle progression by inhibiting not only CDK4-pRb kinase activity but also by modulating CDK7-CTD kinase activity. Regulation of CDK7-CTD kinase activity by p16INK4A thus may represent an alternative pathway for controlling cell cycle progression.

scholarly journals The highly conserved N-terminal domains of histones H3 and H4 are required for normal cell cycle progression

1991 ◽  
Vol 11 (8) ◽  
pp. 4111-4120
Author(s):  
B A Morgan ◽  
B A Mittman ◽  
M M Smith
Keyword(s):  
Cell Cycle ◽  
Normal Cell ◽  
Cell Cycle Progression ◽  
Histone H3 ◽  
Temperature Sensitive ◽  
Histone H4 ◽  
Cycle Progression ◽  
Terminal Domain ◽  
Normal Cell Cycle ◽  
Terminal Domains

The N-terminal domains of the histones H3 and H4 are highly conserved throughout evolution. Mutant alleles deleted for these N-terminal domains were constructed in vitro and examined for function in vivo in Saccharomyces cerevisiae. Cells containing a single deletion allele of either histone H3 or histone H4 were viable. Deletion of the N-terminal domain of histone H4 caused cells to become sterile and temperature sensitive for growth. The normal cell cycle progression of these cells was also altered, as revealed by a major delay in progression through the G2 + M periods. Deletion of the N-terminal domain of histone H3 had only minor effects on mating and the temperature-sensitive growth of mutant cells. However, like the H4 mutant, the H3 mutants had a significant delay in completing the G2 + M periods of the division cycle. Double mutants containing N-terminal domain deletions of both histone H3 and histone H4 were inviable. The phenotypes of cells subject to this synthetic lethality suggest that the N-terminal domains are required for functions essential throughout the cell division cycle and provide genetic evidence that histones are randomly distributed during chromosome replication.

scholarly journals Mammalian cryptochromes impinge on cell cycle progression in a circadian clock-independent manner

Cell Cycle ◽  
2011 ◽  
Vol 10 (21) ◽  
pp. 3788-3797 ◽  
Author(s):  
Eugin Destici ◽  
Małgorzata Oklejewicz ◽  
Shoko Saito ◽  
Gijsbertus T.J. van der Horst
Keyword(s):  
Cell Cycle ◽  
Circadian Clock ◽  
Cell Cycle Progression ◽  
Independent Manner ◽  
Cycle Progression

scholarly journals Regulated Expression of Focal Adhesion Kinase-Related Nonkinase, the Autonomously Expressed C-Terminal Domain of Focal Adhesion Kinase

1999 ◽  
Vol 19 (9) ◽  
pp. 6120-6129 ◽  
Author(s):  
Kate Nolan ◽  
Judith Lacoste ◽  
J. Thomas Parsons
Keyword(s):  
Cell Cycle ◽  
Cell Adhesion ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Cell Cycle Progression ◽  
Negative Regulator ◽  
Mouse Lung ◽  
Cycle Progression ◽  
Terminal Domain ◽  
Mouse Tissues

ABSTRACT Focal adhesion kinase (FAK) has been implicated in cellular processes that control cell adhesion, migration, cell cycle progression, and apoptosis. FRNK (FAK-related nonkinase) is the autonomously expressed, noncatalytic C-terminal portion of FAK. When ectopically expressed in cells, FRNK has been shown to act as a negative regulator of FAK activity, inhibiting cell spreading, migration, and cell cycle progression. The mechanisms that regulate FRNK expression during embryonic development and the functional role of FRNK in normal cell homeostasis remain poorly understood. Herein we show that FRNK expression in chicken cells is directed by an alternative promoter residing within an intron of FAK, positioned 3′ of the exon encoding sequences for the catalytic domain and 5′ of the exon encoding sequences for the C-terminal domain of FAK (e.g., FRNK). Using probes specific for FRNK, we show that FRNK expression occurs early in chicken embryogenesis, being readily detected at day 3, 6, or 9. Late in embryogenesis, at day 18, FRNK is expressed in a tissue-specific manner, predominately in lung and intestine cells. Western blot analysis of mouse tissues with a FAK-specific antibody revealed the expression of FRNK in the mouse lung. Reverse transcriptase PCR analysis of mouse lung RNA revealed the presence of spliced FRNK mRNAs containing 5′ untranslated sequences derived from a positionally conserved exon present in the mouse genome. FAK is the first example of a tyrosine kinase regulated by a domain under the control of an alternative intronic promoter. It is also the first example of a focal adhesion-associated protein regulated by such a mechanism and thus represents a novel means for the modulation of cell adhesion signaling.

scholarly journals Cyclin N-Terminal Domain-Containing 1 (CNTD1) coordinates meiotic crossover formation with cell cycle progression in a cyclin-independent manner

2019 ◽  
Author(s):  
Stephen Gray ◽  
Emerson R. Santiago ◽  
Joshua S. Chappie ◽  
Paula E. Cohen
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Dna Double Strand Breaks ◽  
Independent Manner ◽  
Cellular Division ◽  
Cycle Progression ◽  
Prophase I ◽  
Subsequent Degradation ◽  
Factor C

AbstractDuring meiotic prophase I, programmed DNA double-strand breaks repair as non-crossover or crossover events, the latter predominantly occurring via the Class I crossover pathway and requiring the cyclin family member CNTD1. Using an epitope-tagged Cntd1 allele, we show that mouse CNTD1 exists in vivo as a short isoform that lacks the predicted N-terminal cyclin domain and does not bind cyclin-dependent kinases. Instead, we find that CNTD1 associates with Replication Factor C to drive crossover formation and the Skp1-Cullin1-F-Box complex to regulate ubiquitination and subsequent degradation of the WEE1 kinase, thereby indirectly modulating cell cycle progression. We propose that these interactions enable CNTD1 to orchestrate the steps of prophase I and coordinate crossover formation with cellular division.

scholarly journals Tumor Milieu Controlled by RB Tumor Suppressor

2020 ◽  
Vol 21 (7) ◽  
pp. 2450 ◽  
Author(s):  
Shunsuke Kitajima ◽  
Fengkai Li ◽  
Chiaki Takahashi
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Independent Manner ◽  
Cycle Progression ◽  
Accelerated Proliferation ◽  
A Cell ◽  
Metastatic Activity ◽  
Rb Gene ◽  
E2f Transcription Factors

The RB gene is one of the most frequently mutated genes in human cancers. Canonically, RB exerts its tumor suppressive activity through the regulation of the G1/S transition during cell cycle progression by modulating the activity of E2F transcription factors. However, aberration of the RB gene is most commonly detected in tumors when they gain more aggressive phenotypes, including metastatic activity or drug resistance, rather than accelerated proliferation. This implicates RB controls’ malignant progression to a considerable extent in a cell cycle-independent manner. In this review, we highlight the multifaceted functions of the RB protein in controlling tumor lineage plasticity, metabolism, and the tumor microenvironment (TME), with a focus on the mechanism whereby RB controls the TME. In brief, RB inactivation in several types of cancer cells enhances production of pro-inflammatory cytokines, including CCL2, through upregulation of mitochondrial reactive oxygen species (ROS) production. These factors not only accelerate the growth of cancer cells in a cell-autonomous manner, but also stimulate non-malignant cells in the TME to generate a pro-tumorigenic niche in a non-cell-autonomous manner. Here, we discuss the biological and pathological significance of the non-cell-autonomous functions of RB and attempt to predict their potential clinical relevance to cancer immunotherapy.

scholarly journals Phosphorylation-Independent Inhibition of Cdc28p by the Tyrosine Kinase Swe1p in the Morphogenesis Checkpoint

1999 ◽  
Vol 19 (9) ◽  
pp. 5981-5990 ◽  
Author(s):  
John N. McMillan ◽  
Rey A. L. Sia ◽  
Elaine S. G. Bardes ◽  
Daniel J. Lew
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Single Copy ◽  
Cyclin Dependent Kinase ◽  
Independent Manner ◽  
Cycle Progression ◽  
Checkpoint Response ◽  
Inhibitory Pathways ◽  
Morphogenesis Checkpoint

ABSTRACT The morphogenesis checkpoint in budding yeast delays cell cycle progression in G2 when the actin cytoskeleton is perturbed, providing time for cells to complete bud formation prior to mitosis. Checkpoint-induced G2 arrest involves the inhibition of the master cell cycle regulatory cyclin-dependent kinase, Cdc28p, by the Wee1 family kinase Swe1p. Results of experiments using a nonphosphorylatable CDC28Y19F allele suggested that the checkpoint stimulated two inhibitory pathways, one that promoted phosphorylation at tyrosine 19 (Y19) and a poorly characterized second pathway that did not require Cdc28p Y19 phosphorylation. We present the results from a genetic screen for checkpoint-defective mutants that led to the repeated isolation of the dominant CDC28E12K allele that is resistant to Swe1p-mediated inhibition. Comparison of this allele with the nonphosphorylatable CDC28Y19F allele suggested that Swe1p is still able to inhibit CDC28Y19F in a phosphorylation-independent manner and that both the Y19 phosphorylation-dependent and -independent checkpoint pathways in fact reflect Swe1p inhibition of Cdc28p. Remarkably, we found that a Swe1p mutant lacking catalytic activity could significantly delay the cell cycle in vivo during a physiological checkpoint response, even when expressed at single copy. The finding that a Wee1 family kinase expressed at physiological levels can inhibit a nonphosphorylatable cyclin-dependent kinase has broad implications for many checkpoint studies using such mutants in other organisms.

scholarly journals The highly conserved N-terminal domains of histones H3 and H4 are required for normal cell cycle progression.

1991 ◽  
Vol 11 (8) ◽  
pp. 4111-4120 ◽  
Author(s):  
B A Morgan ◽  
B A Mittman ◽  
M M Smith
Keyword(s):  
Cell Cycle ◽  
Normal Cell ◽  
Cell Cycle Progression ◽  
Histone H3 ◽  
Temperature Sensitive ◽  
Histone H4 ◽  
Cycle Progression ◽  
Terminal Domain ◽  
Normal Cell Cycle ◽  
Terminal Domains

The N-terminal domains of the histones H3 and H4 are highly conserved throughout evolution. Mutant alleles deleted for these N-terminal domains were constructed in vitro and examined for function in vivo in Saccharomyces cerevisiae. Cells containing a single deletion allele of either histone H3 or histone H4 were viable. Deletion of the N-terminal domain of histone H4 caused cells to become sterile and temperature sensitive for growth. The normal cell cycle progression of these cells was also altered, as revealed by a major delay in progression through the G2 + M periods. Deletion of the N-terminal domain of histone H3 had only minor effects on mating and the temperature-sensitive growth of mutant cells. However, like the H4 mutant, the H3 mutants had a significant delay in completing the G2 + M periods of the division cycle. Double mutants containing N-terminal domain deletions of both histone H3 and histone H4 were inviable. The phenotypes of cells subject to this synthetic lethality suggest that the N-terminal domains are required for functions essential throughout the cell division cycle and provide genetic evidence that histones are randomly distributed during chromosome replication.

scholarly journals Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses

2018 ◽  
Vol 115 (18) ◽  
pp. 4678-4683 ◽  
Author(s):  
Tanggang Deng ◽  
Guobei Yan ◽  
Xin Song ◽  
Lin Xie ◽  
Yu Zhou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Independent Manner ◽  
Cycle Progression ◽  
Dna Damage Responses ◽  
Fate Decision

p21WAF1/CIP1 is a broad-acting cyclin-dependent kinase inhibitor. Its stability is essential for proper cell-cycle progression and cell fate decision. Ubiquitylation by the multiple E3 ubiquitin ligase complexes is the major regulatory mechanism of p21, which induces p21 degradation. However, it is unclear whether ubiquitylated p21 can be recycled. In this study, we report USP11 as a deubiquitylase of p21. In the nucleus, USP11 binds to p21, catalyzes the removal of polyubiquitin chains conjugated onto p21, and stabilizes p21 protein. As a result, USP11 reverses p21 polyubiquitylation and degradation mediated by SCFSKP2, CRL4CDT2, and APC/CCDC20 in a cell-cycle–independent manner. Loss of USP11 causes the destabilization of p21 and induces the G1/S transition in unperturbed cells. Furthermore, p21 accumulation mediated by DNA damage is completely abolished in cells depleted of USP11, which results in abrogation of the G2 checkpoint and induction of apoptosis. Functionally, USP11-mediated stabilization of p21 inhibits cell proliferation and tumorigenesis in vivo. These findings reveal an important mechanism by which p21 can be stabilized by direct deubiquitylation, and they pinpoint a crucial role of the USP11-p21 axis in regulating cell-cycle progression and DNA damage responses.

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