A Function of Fas-Associated Death Domain Protein in Cell Cycle Progression Localized to a Single Amino Acid at Its C-Terminal Region

ABSTRACT Although phosphoinositide 3-kinase (PI 3-kinase) is essential for cell cycle progression, the molecular mechanisms that regulate its diverse biological effects are poorly understood. We demonstrate here that Rb, a key regulator of cell cycle progression, associates with p55 kDa (p55α and p55γ) regulatory subunits of PI 3-kinase in vivo and in vitro. Both confocal microscopy and biochemical analysis demonstrated the presence of p55γ in the nucleus. The 24-amino-acid N-terminal end of p55γ, which is unique among PI 3-kinase regulatory subunits, was sufficient to bind Rb. Addition of serum or growth factors to quiescent cells triggered the dissociation of Rb from p55. Ectopic expression of the 24-amino-acid N-terminal end of p55γ inhibited cell cycle progression, as evidenced by induction of cell growth arrest at the G0/G1 phase, inhibition of DNA synthesis, inhibition of cyclin D and cyclin E promoter activity, and changes in the expression of cell cycle-related proteins. The inhibitory effects of the N-terminal end of p55γ on cell cycle progression depended on the presence of functional Rb. These data demonstrate for the first time an association of p55γ with Rb and show that modification of this association can lead to cell cycle arrest.

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Inhibition of Cellular DNA Synthesis by the Human Cytomegalovirus IE86 Protein Is Necessary for Efficient Virus Replication

Journal of Virology ◽

10.1128/jvi.80.8.3872-3883.2006 ◽

2006 ◽

Vol 80 (8) ◽

pp. 3872-3883 ◽

Cited By ~ 43

Author(s):

Dustin T. Petrik ◽

Kimberly P. Schmitt ◽

Mark F. Stinski

Keyword(s):

Cell Cycle ◽

Dna Synthesis ◽

Human Cytomegalovirus ◽

Cell Cycle Progression ◽

Cell Cycle Control ◽

Single Amino Acid ◽

Cycle Progression ◽

Artificial Chromosomes ◽

Early Genes ◽

Cellular Dna

ABSTRACT Human cytomegalovirus (HCMV) expresses several proteins that manipulate normal cellular functions, including cellular transcription, apoptosis, immune response, and cell cycle control. The IE2 gene, which is expressed from the HCMV major immediate-early (MIE) promoter, encodes the IE86 protein. IE86 is a multifunctional protein that is essential for viral replication. The functions of IE86 include transactivation of cellular and viral early genes, negative autoregulation of the MIE promoter, induction of cell cycle progression from G0/G1 to G1/S, and arresting cell cycle progression at the G1/S transition in p53-positive human foreskin fibroblast (HFF) cells. Mutations were introduced into the IE2 gene in the context of the viral genome using bacterial artificial chromosomes (BACs). From these HCMV BACs, a recombinant virus (RV) with a single amino acid substitution in the IE86 protein was isolated that replicates slower and to lower titers than wild-type HCMV. HFF cells infected with the Q548R RV undergo cellular DNA synthesis and do not arrest at any point in the cell cycle. The Q548R RV is able to negatively autoregulate the MIE promoter, transactivate viral early genes, activate cellular E2F-responsive genes, and produce infectious virus. This is the first report of a viable recombinant HCMV that is unable to inhibit cellular DNA synthesis in infected HFF cells.

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The N-Terminal Region of the Polo Kinase Cdc5 is Required for Downregulation of the Meiotic Recombination Checkpoint

Cells ◽

10.3390/cells10102561 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2561

Author(s):

Sara González-Arranz ◽

Isabel Acosta ◽

Jesús A. Carballo ◽

Beatriz Santos ◽

Pedro A. San-Segundo

Keyword(s):

Cell Cycle ◽

Meiotic Recombination ◽

Cell Cycle Progression ◽

Cell Cycle Control ◽

Terminal Region ◽

Cycle Progression ◽

Protein Levels ◽

Additional Layer ◽

C Complex ◽

Recombination Checkpoint

During meiosis, the budding yeast polo-like kinase Cdc5 is a crucial driver of the prophase I to meiosis I (G2/M) transition. The meiotic recombination checkpoint restrains cell cycle progression in response to defective recombination to ensure proper distribution of intact chromosomes to the gametes. This checkpoint detects unrepaired DSBs and initiates a signaling cascade that ultimately inhibits Ndt80, a transcription factor required for CDC5 gene expression. Previous work revealed that overexpression of CDC5 partially alleviates the checkpoint-imposed meiotic delay in the synaptonemal complex-defective zip1Δ mutant. Here, we show that overproduction of a Cdc5 version (Cdc5-ΔN70), lacking the N-terminal region required for targeted degradation of the protein by the APC/C complex, fails to relieve the zip1Δ-induced meiotic delay, despite being more stable and reaching increased protein levels. However, precise mutation of the consensus motifs for APC/C recognition (D-boxes and KEN) has no effect on Cdc5 stability or function during meiosis. Compared to the zip1Δ single mutant, the zip1Δ cdc5-ΔN70 double mutant exhibits an exacerbated meiotic block and reduced levels of Ndt80 consistent with persistent checkpoint activity. Finally, using a CDC5-inducible system, we demonstrate that the N-terminal region of Cdc5 is essential for its checkpoint erasing function. Thus, our results unveil an additional layer of regulation of polo-like kinase function in meiotic cell cycle control.

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Preoptic Regulatory Factor-2, a Rhogap Domain Protein that Modifies Cell Cycle Progression and Apoptosis in the CNS

Stem Cells and Cancer Stem Cells, Volume 12 - Stem Cells and Cancer Stem Cells ◽

10.1007/978-94-017-8032-2_19 ◽

2013 ◽

pp. 219-230 ◽

Cited By ~ 1

Author(s):

Felicia V. Nowak

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Regulatory Factor ◽

Cycle Progression ◽

Domain Protein

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A novel role for methyl CpG-binding domain protein 3, a component of the histone deacetylase complex, in regulation of cell cycle progression and cell death

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2008.11.079 ◽

2009 ◽

Vol 378 (3) ◽

pp. 332-337 ◽

Cited By ~ 7

Author(s):

Eun Joo Noh ◽

Dae-Sik Lim ◽

Jong-Soo Lee

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Histone Deacetylase ◽

Cell Cycle Progression ◽

Binding Domain ◽

Cycle Progression ◽

Domain Protein ◽

Regulation Of Cell Cycle

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Convergence of Alarmone and Cell Cycle Signaling from Trans-Encoded Sensory Domains

mBio ◽

10.1128/mbio.01415-15 ◽

2015 ◽

Vol 6 (5) ◽

Cited By ~ 14

Author(s):

Stefano Sanselicio ◽

Patrick H. Viollier

Keyword(s):

Cell Cycle ◽

Stationary Phase ◽

Cell Cycle Progression ◽

Caulobacter Crescentus ◽

Control Cell ◽

Phase Cell ◽

Cycle Progression ◽

Content Type ◽

Cell Cycle Regulator ◽

Domain Protein

ABSTRACT Despite the myriad of different sensory domains encoded in bacterial genomes, only a few are known to control the cell cycle. Here, suppressor genetics was used to unveil the regulatory interplay between the PAS (Per-Arnt-Sim) domain protein MopJ and the uncharacterized GAF (cyclic GMP-phosphodiesterase–adenylyl cyclase–FhlA) domain protein PtsP, which resembles an alternative component of the phosphoenolpyruvate (PEP) transferase system. Both of these systems indirectly target the Caulobacter crescentus cell cycle master regulator CtrA, but in different ways. While MopJ acts on CtrA via the cell cycle kinases DivJ and DivL, which control the removal of CtrA at the G1-S transition, our data show that PtsP signals through the conserved alarmone (p)ppGpp, which prevents CtrA cycling under nutritional stress and in stationary phase. We found that PtsP interacts genetically and physically with the (p)ppGpp synthase/hydrolase SpoT and that it modulates several promoters that are directly activated by the cell cycle transcriptional regulator GcrA. Thus, parallel systems integrate nutritional and systemic signals within the cell cycle transcriptional network, converging on the essential alphaproteobacterial regulator CtrA while also affecting global cell cycle transcription in other ways. IMPORTANCE Many alphaproteobacteria divide asymmetrically, and their cell cycle progression is carefully regulated. How these bacteria control the cell cycle in response to nutrient limitation is not well understood. Here, we identify a multicomponent signaling pathway that acts on the cell cycle when nutrients become scarce in stationary phase. We show that efficient accumulation of the master cell cycle regulator CtrA in stationary-phase Caulobacter crescentus cells requires the previously identified stationary-phase/cell cycle regulator MopJ as well as the phosphoenolpyruvate protein phosphotransferase PtsP, which acts via the conserved (p)ppGpp synthase SpoT. We identify cell cycle-regulated promoters that are affected by this pathway, providing an explanation of how (p)ppGpp-signaling might couple starvation to control cell cycle progression in Caulobacter spp. and likely other Alphaproteobacteria. This pathway has the potential to integrate carbon fluctuation into cell cycle control, since in phosphotransferase systems it is the glycolytic product phosphenolpyruvate (PEP) rather than ATP that is used as the phosphor donor for phosphorylation.

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