scholarly journals High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1.

1997 ◽  
Vol 17 (9) ◽  
pp. 5588-5597 ◽  
Author(s):  
A Sewing ◽  
B Wiseman ◽  
A C Lloyd ◽  
H Land
Keyword(s):  
Cell Cycle ◽  
Dna Synthesis ◽  
Cell Cycle Arrest ◽  
Expression Patterns ◽  
Cellular Responses ◽  
Specific Cell ◽  
Cyclin D ◽  
Inhibition Of Proliferation ◽  
Cycle Arrest ◽  
Signal Specificity

Activated Raf has been linked to such opposing cellular responses as the induction of DNA synthesis and the inhibition of proliferation. However, it remains unclear how such a switch in signal specificity is regulated. We have addressed this question with a regulatable Raf-androgen receptor fusion protein in murine fibroblasts. We show that Raf can cause a G1-specific cell cycle arrest through induction of p21Cip1. This in turn leads to inhibition of cyclin D- and cyclin E-dependent kinases and an accumulation of hypophosphorylated Rb. Importantly, this behavior can be observed only in response to a strong Raf signal. In contrast, moderate Raf activity induces DNA synthesis and is sufficient to induce cyclin D expression. Therefore, Raf signal specificity can be determined by modulation of signal strength presumably through the induction of distinct protein expression patterns. Similar to induction of Raf, a strong induction of activated Ras via a tetracycline-dependent promoter also causes inhibition of proliferation and p21Cip1 induction at high expression levels. Thus, p21Cip1 plays a key role in determining cellular responses to Ras and Raf signalling. As predicted by this finding we show that Ras and loss of p21 cooperate to confer a proliferative advantage to mouse embryo fibroblasts.

scholarly journals DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A

2020 ◽  
Author(s):  
Kelly E. Leon ◽  
Raquel Buj ◽  
Elizabeth Lesko ◽  
Erika S. Dahl ◽  
Chi-Wei Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Epigenetic Regulation ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Dependent Manner ◽  
Inhibition Of Proliferation ◽  
Cycle Arrest ◽  
Secretory Phenotype ◽  
Negative Side Effects

AbstractCellular senescence is characterized as a stable cell cycle arrest that can occur as a stress response associated with oncogenic activation, termed oncogene-induced senescence (OIS). Cells undergoing OIS acquire a unique microenvironment termed the senescence-associated secretory phenotype (SASP), which can be both beneficial and detrimental in a context-dependent manner. Additionally, senescent cells are characterized by robust changes in their epigenome. Here, we globally assessed the histone landscape of cells induced to senesce by oncogenic RAS and discovered a novel epigenetic regulatory mechanism of the key SASP regulator IL1A. OIS cells displayed increased di- and tri-methylation of histone H3 lysine 79 (H3K79me2/3), two active histone marks. Depletion of the H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) during OIS resulted in decreased H3K79me2/3 occupancy at the IL1A gene locus, which corresponded to decreased IL1A mRNA and cell surface expression. Decreased expression and secretion of downstream cytokines without a change in senescence markers were also observed upon DOT1L depletion. Overexpression of DOT1L increased H3K79me2/3 occupancy at the IL1A locus and upregulated the SASP, indicating that DOT1L is both necessary and sufficient for SASP gene expression. Mechanistically, we found that STING, an essential mediator of SASP transcription, is upstream of DOT1L in the epigenetic regulation of the SASP. Together, our studies establish DOT1L as an epigenetic regulator of the SASP whose expression is uncoupled from the senescence-associated cell cycle arrest, providing a potential strategy to inhibit the negative side effects of senescence while maintaining the beneficial inhibition of proliferation.

scholarly journals Ceramide signals for initiation of yeast mating-specific cell cycle arrest

Cell Cycle ◽  
2016 ◽  
Vol 15 (3) ◽  
pp. 441-454 ◽  
Author(s):  
Michelle L. Villasmil ◽  
Jamie Francisco ◽  
Christina Gallo-Ebert ◽  
Melissa Donigan ◽  
Hsing-Yin Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Specific Cell ◽  
Cycle Arrest ◽  
Yeast Mating

scholarly journals MyoD induced cell cycle arrest is associated with increased nuclear affinity of the Rb protein.

1993 ◽  
Vol 4 (7) ◽  
pp. 705-713 ◽  
Author(s):  
A M Thorburn ◽  
P A Walton ◽  
J R Feramisco
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Dna Synthesis ◽  
Cell Cycle Arrest ◽  
S Phase ◽  
Tumor Suppressor Protein ◽  
G1 Phase ◽  
Induced Expression ◽  
Rb Protein ◽  
Cycle Arrest

In studying the mechanism through which the myogenic determination protein MyoD prevents entry into the S phase of the cell cycle, we have found a relationship between MyoD and the retinoblastoma (Rb) tumor suppressor protein. By direct needle microinjection of purified recombinant MyoD protein into quiescent fibroblasts, which were then induced to proliferate by serum, we found that MyoD arrested progression of the cell cycle, in agreement with studies utilizing expression constructs for MyoD. By studying temporal changes in cells injected with MyoD protein, it was found that MyoD did not prevent serum induced expression of the protooncogene c-Fos, an event that occurs in the G0 to G1 transition of the cycle. Injection of the MyoD protein as late as 8 h after the addition of serum still caused an inhibition in DNA synthesis, suggesting that MyoD inhibits the G1 to S transition as opposed to the G0 to G1 transition. MyoD injection did not prevent the expression of cyclin A. However MyoD injection did result in a block in the increase in Rb extractibility normally seen in late G1 phase cells. As this phenomenon is associated with the hyperphosphorylation of Rb at this point in the cell cycle and is correlated with progression into S phase, this provides further evidence that MyoD blocks the cycle late in G1.

scholarly journals DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A

2021 ◽  
Vol 220 (8) ◽  
Author(s):  
Kelly E. Leon ◽  
Raquel Buj ◽  
Elizabeth Lesko ◽  
Erika S. Dahl ◽  
Chi-Wei Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Dependent Manner ◽  
Inhibition Of Proliferation ◽  
Cycle Arrest ◽  
Secreted Factors ◽  
Secretory Phenotype ◽  
Negative Side Effects ◽  
Potential Strategy ◽  
Necessary And Sufficient

Oncogene-induced senescence (OIS) is a stable cell cycle arrest that occurs in normal cells upon oncogene activation. Cells undergoing OIS express a wide variety of secreted factors that affect the senescent microenvironment termed the senescence-associated secretory phenotype (SASP), which is beneficial or detrimental in a context-dependent manner. OIS cells are also characterized by marked epigenetic changes. We globally assessed histone modifications of OIS cells and discovered an increase in the active histone marks H3K79me2/3. The H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) was necessary and sufficient for increased H3K79me2/3 occupancy at the IL1A gene locus, but not other SASP genes, and was downstream of STING. Modulating DOT1L expression did not affect the cell cycle arrest. Together, our studies establish DOT1L as an epigenetic regulator of the SASP, whose expression is uncoupled from the senescence-associated cell cycle arrest, providing a potential strategy to inhibit the negative side effects of senescence while maintaining the beneficial inhibition of proliferation.

scholarly journals Cytolethal distending toxin A, B and C subunit proteins are necessary for the genotoxic effect of Escherichia coli CDT-V

2015 ◽  
Vol 63 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Frederic Taieb ◽  
Domonkos Sváb ◽  
Claude Watrin ◽  
Eric Oswald ◽  
István Tóth
Keyword(s):  
Escherichia Coli ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Pathogenic Bacteria ◽  
Genotoxic Effect ◽  
Specific Cell ◽  
Protein Subunits ◽  
Cycle Arrest ◽  
Wide Range ◽  
C Subunit

Cytolethal distending toxins (CDT) are considered the prototype of inhibitory cyclomodulins, and are produced by a wide range of Gram-negative pathogenic bacteria, includingEscherichia colistrains of various sero- and pathotypes. CDT is a heterotripartite toxin consisting of three protein subunits, CdtA, CdtB and CdtC. The active subunit, CdtB has DNase activity and causes DNA damage and cell cycle arrest in the target cell. However, several studies have highlighted different roles for CdtA and CdtC subunits. In order to reveal the necessity of CdtA and CdtC subunit proteins in the CDT-specific phenotype, expression clones containing thecdt-Vsubunit genes were constructed. Using cell culture assays, we demonstrated that clones expressing only the CdtB subunit or in combination with only CdtA or CdtC were unable to trigger the specific cell cycle arrest and changes in cell morphology in HeLa cells. At the same time, the recombinant clone harbouring the wholecdt-Voperon caused all the CDT-associated characteristic phenotypes. All these results verify that all the three CDT subunit proteins are necessary for the genotoxic effect caused by CDT-V.

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