scholarly journals The Epstein-Barr Virus Immediate-Early Protein BZLF1 Induces Expression of E2F-1 and Other Proteins Involved in Cell Cycle Progression in Primary Keratinocytes and Gastric Carcinoma Cells

2002 ◽  
Vol 76 (24) ◽  
pp. 12543-12552 ◽  
Author(s):  
Amy Mauser ◽  
Elizabeth Holley-Guthrie ◽  
Adam Zanation ◽  
Wendall Yarborough ◽  
William Kaufmann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
Human Fibroblasts ◽  
Cell Types ◽  
S Phase ◽  
Cycle Progression ◽  
Stem Loop ◽  
Barr Virus ◽  
Early Protein

ABSTRACT The Epstein-Barr virus (EBV) immediate-early protein BZLF1 mediates the switch between the latent and lytic forms of EBV infection and has been previously shown to induce a G1/S block in cell cycle progression in some cell types. To examine the effect of BZLF1 on cellular gene expression, we performed microarray analysis on telomerase-immortalized human keratinocytes that were mock infected or infected with a control adenovirus vector (AdLacZ) or a vector expressing the EBV BZLF1 protein (AdBZLF1). Cellular genes activated by BZLF1 expression included E2F-1, cyclin E, Cdc25A, and a number of other genes involved in cell cycle progression. Immunoblot analysis confirmed that BZLF1 induced expression of E2F-1, cyclin E, Cdc25A, and stem loop binding protein (a protein known to be primarily expressed during S phase) in telomerase-immortalized keratinocytes. Similarly, BZLF1 increased expression of E2F-1, cyclin E, and stem loop binding protein (SLBP) in primary tonsil keratinocytes. In contrast, BZLF1 did not induce E2F-1 expression in normal human fibroblasts. Cell cycle analysis revealed that while BZLF1 dramatically blocked G1/S progression in normal human fibroblasts, it did not significantly affect cell cycle progression in primary human tonsil keratinocytes. Furthermore, in EBV-infected gastric carcinoma cells, the BZLF1-positive cells had an increased number of cells in S phase compared to the BZLF1-negative cells. Thus, in certain cell types (but not others), BZLF1 enhances expression of cellular proteins associated with cell cycle progression, which suggests that an S-phase-like environment may be advantageous for efficient lytic EBV replication in some cell types.

scholarly journals HTLV-I p30 inhibits multiple S phase entry checkpoints, decreases cyclin E-CDK2 interactions and delays cell cycle progression

2010 ◽  
Vol 9 (1) ◽  
pp. 302 ◽  
Author(s):  
Hicham H Baydoun ◽  
Joanna Pancewicz ◽  
XueTao Bai ◽  
Christophe Nicot
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
S Phase ◽  
Cycle Progression ◽  
Phase Entry

scholarly journals Human Cytomegalovirus UL69 Protein Induces Cells To Accumulate in G1 Phase of the Cell Cycle

1999 ◽  
Vol 73 (1) ◽  
pp. 676-683 ◽  
Author(s):  
Mansuo Lu ◽  
Thomas Shenk
Keyword(s):  
Cell Cycle ◽  
Human Cytomegalovirus ◽  
Cell Cycle Progression ◽  
Human Fibroblasts ◽  
Protein A ◽  
S Phase ◽  
Cycle Progression ◽  
Multiple Points ◽  
Cell Cycle Block ◽  
Arrest Cell Cycle Progression

ABSTRACT Earlier studies have revealed that human cytomegalovirus rapidly inhibits the growth of fibroblasts, blocking cell cycle progression at multiple points, including the G1-to-S-phase transition. The present study demonstrates that the UL69 protein, a virus-encoded constituent of the virion, is able to arrest cell cycle progression when introduced into uninfected cells. Expression of the UL69 protein causes U2 OS cells and primary human fibroblasts to accumulate within the G1 compartment of the cell cycle, and serum fails to induce the progression of quiescent human fibroblasts into the S phase when the protein is present. Therefore, the UL69 protein is at least partially responsible for the cell cycle block that is instituted after infection of permissive cells with human cytomegalovirus.

scholarly journals Golgi-associated RhoBTB3 targets Cyclin E for ubiquitylation and promotes cell cycle progression

2013 ◽  
Vol 203 (2) ◽  
pp. 233-250 ◽  
Author(s):  
Albert Lu ◽  
Suzanne R. Pfeffer
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
Cell Cycle Control ◽  
S Phase ◽  
Cycle Progression ◽  
Ubiquitin Ligase Complex ◽  
Golgi Fragmentation ◽  
Ring E3 ◽  
Normal Cell Cycle

Cyclin E regulates the cell cycle transition from G1 to S phase and is degraded before entry into G2 phase. Here we show that RhoBTB3, a Golgi-associated, Rho-related ATPase, regulates the S/G2 transition of the cell cycle by targeting Cyclin E for ubiquitylation. Depletion of RhoBTB3 arrested cells in S phase, triggered Golgi fragmentation, and elevated Cyclin E levels. On the Golgi, RhoBTB3 bound Cyclin E as part of a Cullin3 (CUL3)-dependent RING–E3 ubiquitin ligase complex comprised of RhoBTB3, CUL3, and RBX1. Golgi association of this complex was required for its ability to catalyze Cyclin E ubiquitylation and allow normal cell cycle progression. These experiments reveal a novel role for a Ras superfamily member in catalyzing Cyclin E turnover during S phase, as well as an unexpected, essential role for the Golgi as a ubiquitylation platform for cell cycle control.

Phospholipase Cδ1 regulates cell proliferation and cell-cycle progression from G1- to S-phase by control of cyclin E–CDK2 activity

2008 ◽  
Vol 415 (3) ◽  
pp. 439-448 ◽  
Author(s):  
Katherine A. Kaproth-Joslin ◽  
Xiangquan Li ◽  
Sarah E. Reks ◽  
Grant G. Kelley
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Cyclin E ◽  
Critical Role ◽  
S Phase ◽  
G1 Phase ◽  
Serum Starvation ◽  
Cycle Progression ◽  
Cdk2 Activity

In the present study, we examined the role of PLCδ1 (phospholipase C δ1) in the regulation of cellular proliferation. We demonstrate that RNAi (RNA interference)-mediated knockdown of endogenous PLCδ1, but not PLCβ3 or PLCϵ, induces a proliferation defect in Rat-1 and NIH 3T3 fibroblasts. The decreased proliferation was not due to an induction of apoptosis or senescence, but was associated with an approx. 60% inhibition of [3H]thymidine incorporation. Analysis of the cell cycle with BrdU (bromodeoxyuridine)/propidium iodide-labelled FACS (fluorescence-activated cell sorting) demonstrated an accumulation of cells in G0/G1-phase and a corresponding decrease in cells in S-phase. Further examination of the cell cycle after synchronization by serum-starvation demonstrated normal movement through G1-phase but delayed entry into S-phase. Consistent with these findings, G1 cyclin (D2 and D3) and CDK4 (cyclin-dependent kinase 4) levels and associated kinase activity were not affected. However, cyclin E-associated CDK2 activity, responsible for G1-to-S-phase progression, was inhibited. This decreased activity was accompanied by unchanged CDK2 protein levels and paradoxically elevated cyclin E and cyclin E-associated CDK2 levels, suggesting inhibition of the cyclin E–CDK2 complex. This inhibition was not due to altered stimulatory or inhibitory phosphorylation of CDK2. However, p27, a Cip/Kip family CKI (CDK inhibitor)-binding partner, was elevated and showed increased association with CDK2 in PLCδ1-knockdown cells. The result of the present study demonstrate a novel and critical role for PLCδ1 in cell-cycle progression from G1-to-S-phase through regulation of cyclin E–CDK2 activity and p27 levels.

scholarly journals Ki-67 contributes to normal cell cycle progression and inactive X heterochromatin in p21 checkpoint-proficient human cells

2017 ◽  
Author(s):  
Xiaoming Sun ◽  
Aizhan Bizhanova ◽  
Timothy D. Matheson ◽  
Jun Yu ◽  
Lihua Julie Zhu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Nuclear Lamina ◽  
Cell Types ◽  
S Phase ◽  
Human Cells ◽  
Cell Cycle Distribution ◽  
Ki 67 ◽  
Primary Fibroblast ◽  
Cycle Progression

AbstractKi-67 protein is widely used as a tumor proliferation marker. However, whether Ki-67 affects cell cycle progression has been controversial. Here, we demonstrate that depletion of Ki-67 in human hTERT-RPE1, WI-38, IMR90, hTERT-BJ cell lines and primary fibroblast cells slowed entry into S phase and coordinately downregulated genes related to DNA replication. Some gene expression changes were partially relieved in Ki-67-depleted hTERT-RPE1 cells by co-depletion of the Rb checkpoint protein, but more thorough suppression of the transcriptional and cell cycle defects was observed upon depletion of cell cycle inhibitor p21. Notably, induction of p21 upon depletion of Ki-67 was a consistent hallmark of cell types in which transcription and cell cycle distribution were sensitive to Ki-67; these responses were absent in cells that did not induce p21. Furthermore, upon Ki-67 depletion, a subset of inactive × (Xi) chromosomes in female hTERT-RPE1 cells displayed several features of compromised heterochromatin maintenance, including decreased H3K27me3 and H4K20me1 labeling. These chromatin alterations were limited to Xi chromosomes localized away from the nuclear lamina and were not observed in checkpoint-deficient 293T cells. Altogether, our results indicate that Ki-67 integrates normal S phase progression and Xi heterochromatin maintenance in p21 checkpoint-proficient human cells.

scholarly journals Ki-67 Contributes to Normal Cell Cycle Progression and Inactive X Heterochromatin in p21 Checkpoint-Proficient Human Cells

2017 ◽  
Vol 37 (17) ◽  
Author(s):  
Xiaoming Sun ◽  
Aizhan Bizhanova ◽  
Timothy D. Matheson ◽  
Jun Yu ◽  
Lihua Julie Zhu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Nuclear Lamina ◽  
Cell Types ◽  
S Phase ◽  
Human Cells ◽  
Cell Cycle Distribution ◽  
Ki 67 ◽  
Primary Fibroblast ◽  
Cycle Progression

ABSTRACT The Ki-67 protein is widely used as a tumor proliferation marker. However, whether Ki-67 affects cell cycle progression has been controversial. Here we demonstrate that depletion of Ki-67 in human hTERT-RPE1, WI-38, IMR90, and hTERT-BJ cell lines and primary fibroblast cells slowed entry into S phase and coordinately downregulated genes related to DNA replication. Some gene expression changes were partially relieved in Ki-67-depleted hTERT-RPE1 cells by codepletion of the Rb checkpoint protein, but more thorough suppression of the transcriptional and cell cycle defects was observed upon depletion of the cell cycle inhibitor p21. Notably, induction of p21 upon depletion of Ki-67 was a consistent hallmark of cell types in which transcription and cell cycle distribution were sensitive to Ki-67; these responses were absent in cells that did not induce p21. Furthermore, upon Ki-67 depletion, a subset of inactive X (Xi) chromosomes in female hTERT-RPE1 cells displayed several features of compromised heterochromatin maintenance, including decreased H3K27me3 and H4K20me1 labeling. These chromatin alterations were limited to Xi chromosomes localized away from the nuclear lamina and were not observed in checkpoint-deficient 293T cells. Altogether, our results indicate that Ki-67 integrates normal S-phase progression and Xi heterochromatin maintenance in p21 checkpoint-proficient human cells.

COX-2 expression and cell cycle progression in human fibroblasts

2001 ◽  
Vol 281 (1) ◽  
pp. C188-C194 ◽  
Author(s):  
Derek W. Gilroy ◽  
Michael A. Saunders ◽  
Kenneth K. Wu
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Human Fibroblasts ◽  
S Phase ◽  
Prostaglandin E ◽  
Cycle Progression ◽  
Proliferation And Apoptosis ◽  
Serum Inhibition ◽  
Cox 2

Cyclooxygenase-2 (COX-2) is continuously expressed in most cancerous cells where it appears to modulate cellular proliferation and apoptosis. However, little is known about the contribution of transient COX-2 induction to cell cycle progression or programmed cell death in primary cells. In this study we determined whether COX-2 regulates proliferation or apoptosis in human fibroblasts. COX-2 mRNA, protein, and prostaglandin E2(PGE2) were not detected in quiescent cells but were expressed during the G0/G1 phase of the cell cycle induced by serum. Inhibition of COX-2 did not alter G0/G1 to S phase transition or induce apoptosis at concentrations that diminished PGE2. Addition of interleukin-1β to serum enhanced COX-2 expression and PGE2 synthesis over that by serum alone but had no effect on the progression of these cells into S phase. Furthermore, platelet-derived growth factor drove the G0 fibroblasts into the cell cycle without inducing detectable levels of COX-2 or PGE2. Collectively, these data show that transient COX-2 expression in primary human fibroblasts does not influence cell cycle progression.

scholarly journals The Human Cytomegalovirus IE86 Protein Can Block Cell Cycle Progression after Inducing Transition into the S Phase of Permissive Cells

2000 ◽  
Vol 74 (15) ◽  
pp. 7108-7118 ◽  
Author(s):  
Eain A. Murphy ◽  
Daniel N. Streblow ◽  
Jay A. Nelson ◽  
Mark F. Stinski
Keyword(s):  
Cell Cycle ◽  
Protein Expression ◽  
Human Cytomegalovirus ◽  
Cell Cycle Progression ◽  
Hcmv Infection ◽  
Fluorescent Protein ◽  
Cell Types ◽  
S Phase ◽  
Cycle Progression ◽  
Green Fluorescent

ABSTRACT Human cytomegalovirus (HCMV) infection of permissive cells has been reported to induce a cell cycle halt. One or more viral proteins may be involved in halting progression at different stages of the cell cycle. We investigated how HCMV infection, and specifically IE86 protein expression, affects the cell cycles of permissive and nonpermissive cells. We used a recombinant virus that expresses the green fluorescent protein (GFP) to determine the effects of HCMV on the cell cycle of permissive cells. Fluorescence by GFP allowed us to select for only productively infected cells. Replication-defective adenovirus vectors expressing the IE72 or IE86 protein were also used to efficiently transduce 95% or more of the cells. The adenovirus-expressed IE86 protein was determined to be functional by demonstrating negative autoregulation of the major immediate-early promoter and activation of an early viral promoter in the context of the viral genome. To eliminate adenovirus protein effects, plasmids expressing GFP for fluorescent selection of only transfected cells and wild-type IE86 protein or a mutant IE86 protein were tested in permissive and nonpermissive cells. HCMV infection induced the entry of U373 cells into the S phase. All permissive cells infected with HCMV were blocked in cell cycle progression and could not divide. After either transduction or transfection and IE86 protein expression, the number of all permissive or nonpermissive cell types in the S phase increased significantly, but the cells could no longer divide. The IE72 protein did not have a significant effect on the S phase. Since IE86 protein inhibits cell cycle progression, the IE2 gene in a human fibroblast IE86 protein-expressing cell line was sequenced. The IE86 protein in these retrovirus-transduced cells has mutations in a critical region of the viral protein. The locations of the mutations and the function of the IE86 protein in controlling cell cycle progression are discussed.

scholarly journals Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of cyclin E-cdk2, and phosphorylation of the retinoblastoma protein.

1996 ◽  
Vol 133 (2) ◽  
pp. 391-403 ◽  
Author(s):  
X Zhu ◽  
M Ohtsubo ◽  
R M Böhmer ◽  
J M Roberts ◽  
R K Assoian
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
Retinoblastoma Protein ◽  
Cell Types ◽  
S Phase ◽  
Cycle Basis ◽  
Nonadherent Cells

Growth factors and cell anchorage jointly regulate transit through G1 in almost all cell types, but the cell cycle basis for this combined requirement remains largely uncharacterized. We show here that cell adhesion and growth factors jointly regulate the cyclin D1- and E-dependent kinases. Adhesion to substratum regulates both the induction and translation of cyclin D1 mRNA. Nonadherent cells fail to phosphorylate the retinoblastoma protein (Rb), and enforced expression of cyclin D1 rescues Rb phosphorylation and entry into S phase when G1 cells are cultured in the absence of substratum. Nonadherent cells also fail to activate the cyclin E-associated kinase, and this effect can be linked to an increased association of the cdk inhibitors, p21 and p27. These data describe a striking convergence in the cell cycle controls used by the two major signal transduction systems responsible for normal and abnormal cell growth. Taken together with our previous studies showing adhesion-dependent expression of cyclin A, they also establish the cell cycle basis for explaining the combined requirement for growth factors and the extracellular matrix in transit through the Rb checkpoint, entry into S phase, and anchorage-dependent growth.

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