scholarly journals The Rice Cyclin-Dependent Kinase –Activating Kinase R2 Regulates S-Phase Progression

2002 ◽  
Vol 14 (1) ◽  
pp. 197-210 ◽  
Author(s):  
Tanja Fabian-Marwedel ◽  
Masaaki Umeda ◽  
Margret Sauter
Keyword(s):  
S Phase ◽  
Cyclin Dependent Kinase ◽  
Phase Progression

scholarly journals The Stress-activated Protein Kinase Hog1 Mediates S Phase Delay in Response to Osmostress

2009 ◽  
Vol 20 (15) ◽  
pp. 3572-3582 ◽  
Author(s):  
Gilad Yaakov ◽  
Alba Duch ◽  
María García-Rubio ◽  
Josep Clotet ◽  
Javier Jimenez ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
S Phase ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Replication Complex ◽  
Extracellular Stimuli ◽  
Phase Progression ◽  
Cell Cycle Machinery

Control of cell cycle progression by stress-activated protein kinases (SAPKs) is essential for cell adaptation to extracellular stimuli. Exposure of yeast to osmostress activates the Hog1 SAPK, which modulates cell cycle progression at G1 and G2 by the phosphorylation of elements of the cell cycle machinery, such as Sic1 and Hsl1, and by down-regulation of G1 and G2 cyclins. Here, we show that upon stress, Hog1 also modulates S phase progression. The control of S phase is independent of the S phase DNA damage checkpoint and of the previously characterized Hog1 cell cycle targets Sic1 and Hsl1. Hog1 uses at least two distinct mechanisms in its control over S phase progression. At early S phase, the SAPK prevents firing of replication origins by delaying the accumulation of the S phase cyclins Clb5 and Clb6. In addition, Hog1 prevents S phase progression when activated later in S phase or cells containing a genetic bypass for cyclin-dependent kinase activity. Hog1 interacts with components of the replication complex and delays phosphorylation of the Dpb2 subunit of the DNA polymerase. The two mechanisms of Hog1 action lead to delayed firing of origins and prolonged replication, respectively. The Hog1-dependent delay of replication could be important to allow Hog1 to induce gene expression before replication.

scholarly journals Retinoblastoma Tumor Suppressor Protein Signals through Inhibition of Cyclin-Dependent Kinase 2 Activity To Disrupt PCNA Function in S Phase

2001 ◽  
Vol 21 (12) ◽  
pp. 4032-4045 ◽  
Author(s):  
Zvjezdana Sever-Chroneos ◽  
Steven P. Angus ◽  
Anne F. Fribourg ◽  
Huajing Wan ◽  
Ivan Todorov ◽  
...  
Keyword(s):  
Dna Replication ◽  
Tumor Suppressor ◽  
Cyclin A ◽  
S Phase ◽  
Tumor Suppressor Protein ◽  
Cyclin Dependent Kinase ◽  
Retinoblastoma Tumor Suppressor Protein ◽  
Retinoblastoma Tumor Suppressor ◽  
Phase Progression ◽  
Retinoblastoma Tumor

ABSTRACT The retinoblastoma tumor suppressor protein (RB) is a negative regulator of the cell cycle that inhibits both G1 and S-phase progression. While RB-mediated G1 inhibition has been extensively studied, the mechanism utilized for S-phase inhibition is unknown. To delineate the mechanism through which RB inhibits DNA replication, we generated cells which inducibly express a constitutively active allele of RB (PSM-RB). We show that RB-mediated S-phase inhibition does not inhibit the chromatin binding function of MCM2 or RPA, suggesting that RB does not regulate the prereplication complex or disrupt early initiation events. However, activation of RB in S-phase cells disrupts the chromatin tethering of PCNA, a requisite component of the DNA replication machinery. The action of RB was S phase specific and did not inhibit the DNA damage-mediated association of PCNA with chromatin. We also show that RB-mediated PCNA inhibition was dependent on downregulation of CDK2 activity, which was achieved through the downregulation of cyclin A. Importantly, restoration of cyclin-dependent kinase 2 (CDK2)–cyclin A and thus PCNA activity partially restored S-phase progression in the presence of active RB. Therefore, the data presented identify RB-mediated regulation of PCNA activity via CDK2 attenuation as a mechanism through which RB regulates S-phase progression. Together, these findings identify a novel pathway of RB-mediated replication inhibition.

scholarly journals A Key Commitment Step In Erythropoiesis Is Synchronized with the Cell Cycle Clock through Mutual Inhibition Between PU.1 and S-Phase Progression

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 839-839
Author(s):  
Ramona Pop ◽  
Jeffrey R Shearstone ◽  
Qichang Shen ◽  
Ying Liu ◽  
Kelly Hallstrom ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Fetal Liver ◽  
S Phase ◽  
Dna Demethylation ◽  
Cyclin Dependent Kinase ◽  
Mutual Inhibition ◽  
Black Arrow ◽  
Multiple Differentiation ◽  
Phase Progression

Abstract Abstract 839 Hematopoietic progenitors undergo differentiation while navigating several cell division cycles, but it is unknown whether these two processes are functionally coupled. We addressed this question by studying erythropoiesis in mouse fetal liver in vivo. We used flow cytometry and the cell surface markers CD71 and Ter119 to subdivide freshly isolated fetal liver cells into a developmental sequence of six subsets, from the least mature, Subset 0 (S0), to the most mature, Subset 5 (S5). We found that the upregulation of cell surface CD71, which marks the transition from S0 (CD71lowTer119negative) to S1 (CD71highTer119negative), identifies a key S-phase dependent step in erythropoiesis, that precedes, and is essential for, expression of erythroid-specific genes (Figure 1). Specifically, we found that erythroid progenitors at the transition from S0 to S1 are tightly synchronized in S-phase of the last generation of erythroid colony-forming cells (CFU-e). DNA replication within this, but not subsequent cycles, was required for a number of simultaneous committal transitions whose precise timing was previously unknown. These include the onset of erythropoietin dependence, activation of the erythroid master transcriptional regulator GATA-1, and a switch to an active chromatin conformation at the b-globin locus control region (LCR). The S-phase dependent chromatin switch at the b-globin LCR was characterized by the formation of DNase I hypersensitivity sites, by a change in the timing of replication of the b-globin locus, by altered covalent modifications of histone tails, and by the rapid onset of DNA demethylation. An arrest of S-phase progression during the transition from S0 to S1 arrested the formation of DNase I hypersensitivity sites and prevented DNA demethylation. It also halted the subsequent transcription of b-globin and other erythroid genes. By contrast, an arrest of S-phase progression in cells that had already traversed the S0/S1 transition, no longer interfered with the erythroid transcriptional program. Mechanistically, we found that S-phase progression during this key committal step was dependent on downregulation of the cyclin-dependent kinase p57KIP2, and in turn caused the downregulation of PU.1, an antagonist of GATA-1 function. These findings therefore highlight a novel regulatory role for a cyclin-dependent kinase inhibitor early in erythroid maturation, distinct to their known function in cell cycle exit at the end of terminal differentiation. Furthermore, we identified a novel, mutual inhibition between PU.1 expression and S-phase progression, that provides a “synchromesh” mechanism, “locking” the erythroid differentiation program to the cell cycle clock and ensuring precise coordination of critical differentiation events. Figure 1: Regulation of the S0 to S1 transition in fetal liver erythropoiesis. Multiple differentiation milestones are synchronous with early S-phase in the last CFU-e generation (CFU-elast, black arrow), and are dependent on DNA replication. Figure 1:. Regulation of the S0 to S1 transition in fetal liver erythropoiesis. Multiple differentiation milestones are synchronous with early S-phase in the last CFU-e generation (CFU-elast, black arrow), and are dependent on DNA replication. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Distinct Action of the Retinoblastoma Pathway on the DNA Replication Machinery Defines Specific Roles for Cyclin-Dependent Kinase Complexes in Prereplication Complex Assembly and S-Phase Progression

2006 ◽  
Vol 26 (20) ◽  
pp. 7667-7681 ◽  
Author(s):  
Wesley A. Braden ◽  
Jon M. Lenihan ◽  
Zhengdao Lan ◽  
K. Scott Luce ◽  
William Zagorski ◽  
...  
Keyword(s):  
Genome Stability ◽  
Large Fraction ◽  
Critical Role ◽  
S Phase ◽  
Cyclin Dependent Kinase ◽  
Replication Machinery ◽  
Complex Assembly ◽  
Replication Control ◽  
Phase Progression ◽  
Mcm Proteins

ABSTRACT The retinoblastoma (RB) and p16ink4a tumor suppressors are believed to function in a linear pathway that is functionally inactivated in a large fraction of human cancers. Recent studies have shown that RB plays a critical role in regulating S phase as a means for suppressing aberrant proliferation and controlling genome stability. Here, we demonstrate a novel role for p16ink4a in replication control that is distinct from that of RB. Specifically, p16ink4a disrupts prereplication complex assembly by inhibiting mini-chromosome maintenance (MCM) protein loading in G1, while RB was found to disrupt replication in S phase through attenuation of PCNA function. This influence of p16ink4a on the prereplication complex was dependent on the presence of RB and the downregulation of cyclin-dependent kinase (CDK) activity. Strikingly, the inhibition of CDK2 activity was not sufficient to prevent the loading of MCM proteins onto chromatin, which supports a model wherein the composite action of multiple G1 CDK complexes regulates prereplication complex assembly. Additionally, p16ink4a attenuated the levels of the assembly factors Cdt1 and Cdc6. The enforced expression of these two licensing factors was sufficient to restore the assembly of the prereplication complex yet failed to promote S-phase progression due to the continued absence of PCNA function. Combined, these data reveal that RB and p16ink4a function through distinct pathways to inhibit the replication machinery and provide evidence that stepwise regulation of CDK activity interfaces with the replication machinery at two discrete execution points.

scholarly journals A Skp2 autoinduction loop and restriction point control

2007 ◽  
Vol 178 (5) ◽  
pp. 741-747 ◽  
Author(s):  
Yuval Yung ◽  
Janice L. Walker ◽  
James M. Roberts ◽  
Richard K. Assoian
Keyword(s):  
S Phase ◽  
Cyclin Dependent Kinase ◽  
Embryonic Fibroblasts ◽  
Papilloma Virus ◽  
Restriction Point ◽  
Pocket Proteins ◽  
Serum Stimulation ◽  
Point Control ◽  
Phase Progression ◽  
Phase Entry

We describe a self-amplifying feedback loop that autoinduces Skp2 during G1 phase progression. This loop, which contains Skp2 itself, p27kip1 (p27), cyclin E–cyclin dependent kinase 2, and the retinoblastoma protein, is closed through a newly identified, conserved E2F site in the Skp2 promoter. Interference with the loop, by knockin of a Skp2-resistant p27 mutant (p27T187A), delays passage through the restriction point but does not interfere with S phase entry under continuous serum stimulation. Skp2 knock down inhibits S phase entry in nontransformed mouse embryonic fibroblasts but not in human papilloma virus–E7 expressing fibroblasts. We propose that the essential role for Skp2-dependent degradation of p27 is in the formation of an autoinduction loop that selectively controls the transition to mitogen-independence, and that Skp2-dependent proteolysis may be dispensable when pocket proteins are constitutively inactivated.

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