scholarly journals Molecular Insight into How HIV-1 Vpr Protein Impairs Cell Growth through Two Genetically Distinct Pathways

2011 ◽  
Vol 286 (27) ◽  
pp. 23742-23752 ◽  
Author(s):  
Claire Maudet ◽  
Matthieu Bertrand ◽  
Erwann Le Rouzic ◽  
Hichem Lahouassa ◽  
Diana Ayinde ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Colony Formation ◽  
Cell Cycle Progression ◽  
Cycle Arrest ◽  
Cellular Target ◽  
Block Cell Cycle Progression ◽  
The One ◽  
Necessary And Sufficient ◽  
Hiv 1

Vpr, a small HIV auxiliary protein, hijacks the CUL4 ubiquitin ligase through DCAF1 to inactivate an unknown cellular target, leading to cell cycle arrest at the G2 phase and cell death. Here we first sought to delineate the Vpr determinants involved in the binding to DCAF1 and to the target. On the one hand, the three α-helices of Vpr are necessary and sufficient for binding to DCAF1; on the other hand, nonlinear determinants in Vpr are required for binding to the target, as shown by using protein chimeras. We also underscore that a SRIG motif conserved in the C-terminal tail of Vpr proteins from HIV-1/SIVcpz and HIV-2/SIVsmm lineages is critical for G2 arrest. Our results suggest that this motif may be predictive of the ability of Vpr proteins from other SIV lineages to mediate G2 arrest. We took advantage of the characterization of a subset of G2 arrest-defective, but DCAF1 binding-proficient mutants, to investigate whether Vpr interferes with cell viability independently of its ability to induce G2 arrest. These mutants inhibited cell colony formation in HeLa cells and are cytotoxic in lymphocytes, unmasking a G2 arrest-independent cytopathic effect of Vpr. Furthermore these mutants do not block cell cycle progression at the G1 or S phases but trigger apoptosis through caspase 3. Disruption of DCAF1 binding restored efficiency of colony formation. However, DCAF1 binding per se is not sufficient to confer cytopathicity. These data support a model in which Vpr recruits DCAF1 to induce the degradation of two host proteins independently required for proper cell growth.

scholarly journals Antagonism of PP2A is an independent and conserved function of HIV-1 Vif and causes cell cycle arrest

2019 ◽  
Author(s):  
Sara Marelli ◽  
James C Williamson ◽  
Anna V Protasio ◽  
Adi Naamati ◽  
Edward JD Greenwood ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
M Cell ◽  
Regulatory Subunits ◽  
Cycle Arrest ◽  
Identify Amino Acid ◽  
Necessary And Sufficient ◽  
Hiv 1

AbstractThe seminal description of cellular restriction factor APOBEC3G and its antagonism by HIV-1 Vif has underpinned two decades of research on the host-virus interaction. As well as APOBEC3G and its homologues, however, we have recently discovered that Vif is also able to degrade the PPP2R5 family of regulatory subunits of key cellular phosphatase PP2A (PPP2R5A-E) (Greenwood et al., 2016; Naamati et al., 2019). We now identify amino acid polymorphisms at positions 31 and 128 of HIV-1 Vif which selectively regulate the degradation of PPP2R5 family proteins. These residues covary across HIV-1 viruses in vivo, favouring depletion of PPP2R5A-E. Through analysis of point mutants and naturally occurring Vif variants, we further show that degradation of PPP2R5 family subunits is both necessary and sufficient for Vif-dependent G2/M cell cycle arrest. Antagonism of PP2A by HIV-1 Vif is therefore independent of APOBEC3 family proteins, and regulates cell cycle progression in HIV-infected cells.

scholarly journals Antagonism of PP2A is an independent and conserved function of HIV-1 Vif and causes cell cycle arrest

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Sara Marelli ◽  
James C Williamson ◽  
Anna V Protasio ◽  
Adi Naamati ◽  
Edward JD Greenwood ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
M Cell ◽  
Regulatory Subunits ◽  
Cycle Arrest ◽  
Identify Amino Acid ◽  
Necessary And Sufficient ◽  
Hiv 1

The seminal description of the cellular restriction factor APOBEC3G and its antagonism by HIV-1 Vif has underpinned two decades of research on the host-virus interaction. We recently reported that HIV-1 Vif is also able to degrade the PPP2R5 family of regulatory subunits of key cellular phosphatase PP2A (PPP2R5A-E; Greenwood et al., 2016; Naamati et al., 2019). We now identify amino acid polymorphisms at positions 31 and 128 of HIV-1 Vif which selectively regulate the degradation of PPP2R5 family proteins. These residues covary across HIV-1 viruses in vivo, favouring depletion of PPP2R5A-E. Through analysis of point mutants and naturally occurring Vif variants, we further show that degradation of PPP2R5 family subunits is both necessary and sufficient for Vif-dependent G2/M cell cycle arrest. Antagonism of PP2A by HIV-1 Vif is therefore independent of APOBEC3 family proteins, and regulates cell cycle progression in HIV-infected cells.

scholarly journals Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro

Cell Cycle ◽  
2009 ◽  
Vol 8 (6) ◽  
pp. 909-915 ◽  
Author(s):  
Irina N. Alimova ◽  
Bolin Liu ◽  
Zeying Fan ◽  
Susan M. Edgerton ◽  
Thomas Dillon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Breast Cancer Cell ◽  
Colony Formation ◽  
Cancer Cell Growth ◽  
Breast Cancer Cell Growth ◽  
Cycle Arrest

scholarly journals Phosphorylation of Human Immunodeficiency Virus Type 1 Vpr Regulates Cell Cycle Arrest

2000 ◽  
Vol 74 (14) ◽  
pp. 6520-6527 ◽  
Author(s):  
Yi Zhou ◽  
Lee Ratner
Keyword(s):  
Cell Cycle ◽  
Human Immunodeficiency Virus ◽  
Cell Cycle Arrest ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Cycle Progression ◽  
Cycle Arrest ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) Vpr regulates nuclear transport of the viral preintegration complex, G2 cell cycle arrest, and transcriptional transactivation. We asked whether phosphorylation could affect Vpr activity. Vpr was found to be phosphorylated on serine residues in transiently transfected and infected cells. Residues 79, 94, and 96 were all found to be phosphorylated, as assessed by alanine mutations. Mutation of Ser-79 to Ala abrogated effects of Vpr on cell cycle progression, whereas mutation of Ser-94 and Ser-96 had no effect. Simultaneous mutation of all three Vpr serine residues attenuated HIV-1 replication in macrophages, whereas single and double Ser mutations had no effect.

The HGF/c-Met Signaling Pathway in Hodgkin Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1551-1551
Author(s):  
Chuanhui Xu ◽  
Anke Van Den Berg ◽  
Arjan Diepstra ◽  
Miao Wang ◽  
Debora Jong ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Hodgkin Lymphoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
M Cell ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Abstract 1551 Poster Board I-574 Introduction Hodgkin lymphoma (HL) is a B-cell neoplasm characterized by a minority of neoplastic cells, the so-called Hodgkin and Reed-Sternberg (HRS) cells, which are located within an extensive infiltrate of reactive cells. Aberrant signaling of various receptor tyrosine kinases (RTKs) via autocrine or paracrine mechanisms contributes to the survival and proliferation of HRS cells. Activation of the hepatocyte growth factor (HGF)/c-Met signaling pathway has been implicated in the pathophysiology of many cancers, but its role in HL is poorly investigated. In this study, we investigated the expression of c-Met and HGF in HL patient tissues and studied the cell physiological effects of the HGF/c-Met signaling pathway using a c-Met tyrosine kinase inhibitor SU11274 in HL cell lines. Methods The expression of c-Met and HGF in HL patient tissues was studied by immunohistochemistry on a HL tissue microarray. The c-Met expression level was determined by Western blotting, while HGF mRNA and protein levels were measured by quantitative (q)RT-PCR and ELISA in four HL cell lines, i.e. L428, KMH2, L1236 and U-HO1. The effects of SU11274 treatment on the activity of the HGF/c-Met signaling pathway was determined by detection of phosphorylated downstream targets by Western blotting. Effects on cell growth and cell cycle were determined by 3-(4,5- Dimethylthiazol -2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and by flow cytometry with Propidium iodide (PI), respectively. Results C-Met was detected in HRS cells in 55% (26/47) of HL patient tissues. Expression of HGF was detected in HRS cells in 5 c-Met positive and 2 c-Met negative HL patient tissues. C-Met was highly expressed in L428 compared to three other HL cell lines, whereas HGF was highly expressed in KMH2 and not or only weakly in the other three HL cell lines. Detectable levels of phosphorylated c-Met (p-Met) were observed only in L428 consistent with the high basal expression level of c-Met. Phosphorylation of c-Met, Akt and Erk1/2 were upregulated upon HGF stimulation of L428 cells. This activation could be blocked by inhibiting c-Met activation with SU11274. In functional studies, SU11274 suppressed cell growth in L428, promoted G2/M cell cycle arrest after 24h incubation, and induced tetraploidy after 48h. Washing of the cells after induction of G2/M arrest resulted in normal cell cycle progression indicating that the G2/M cell cycle arrest was reversible. Inhibition of PI3K, MEK1/2 and Erk1/2, three downstream targets of the HGF/c-Met signaling pathway, also induced G2/M cell cycle arrest in L428, indicating that these factors are involved in the G2/M cell cycle arrest induced by SU11274. Conclusion Co-expression of c-Met and HGF in HRS cells was observed in 11% of the HL patient tissues and HGF/c-Met signaling pathway regulates cell growth and cell cycle progression in L428 cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Loss of C/EBPα cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage

2005 ◽  
Vol 202 (1) ◽  
pp. 85-96 ◽  
Author(s):  
Bo T. Porse ◽  
David Bryder ◽  
Kim Theilgaard-Mönch ◽  
Marie S. Hasemann ◽  
Kristina Anderson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Regulatory Function ◽  
Neutrophil Granulocyte ◽  
Cycle Arrest ◽  
Myeloid Progenitor ◽  
Enhancer Binding Protein ◽  
Block Cell Cycle Progression

CCAAT/enhancer binding protein (C/EBP)α is a myeloid-specific transcription factor that couples lineage commitment to terminal differentiation and cell cycle arrest, and is found mutated in 9% of patients who have acute myeloid leukemia (AML). We previously showed that mutations which dissociate the ability of C/EBPα to block cell cycle progression through E2F inhibition from its function as a transcriptional activator impair the in vivo development of the neutrophil granulocyte and adipose lineages. We now show that such mutations increase the capacity of bone marrow (BM) myeloid progenitors to proliferate, and predispose mice to a granulocytic myeloproliferative disorder and transformation of the myeloid compartment of the BM. Both of these phenotypes were transplantable into lethally irradiated recipients. BM transformation was characterized by a block in granulocyte differentiation, accumulation of myeloblasts and promyelocytes, and expansion of myeloid progenitor populations—all characteristics of AML. Circulating myeloblasts and hepatic leukocyte infiltration were observed, but thrombocytopenia, anemia, and elevated leukocyte count—normally associated with AML—were absent. These results show that disrupting the cell cycle regulatory function of C/EBPα is sufficient to initiate AML-like transformation of the granulocytic lineage, but only partially the peripheral pathology of AML.

scholarly journals Insulin-Like Growth Factor Binding Protein-5 Interacts with the Vitamin D Receptor and Modulates the Vitamin D Response in Osteoblasts

2007 ◽  
Vol 21 (10) ◽  
pp. 2378-2390 ◽  
Author(s):  
Lynette J. Schedlich ◽  
Anita Muthukaruppan ◽  
Michelle K. O’Han ◽  
Robert C. Baxter
Keyword(s):  
Cell Cycle ◽  
Vitamin D ◽  
Alkaline Phosphatase ◽  
Cell Growth ◽  
Alkaline Phosphatase Activity ◽  
Cell Cycle Progression ◽  
Differentiation Markers ◽  
Cycle Progression ◽  
Bone Differentiation ◽  
Cycle Arrest

Abstract The 1,25 dihydroxyvitamin D3 [1,25(OH)2D3]-induced differentiation of osteoblasts comprises the sequential induction of cell cycle arrest at G0/G1 and the expression of bone matrix proteins. Reports differ on the effects of IGF binding protein (IGFBP)-5 on bone cell growth and osteoblastic function. IGFBP-5 can be growth stimulatory or inhibitory and can enhance or impair osteoblast function. In previous studies, we have shown that IGFBP-5 localizes to the nucleus and interacts with the retinoid receptors. We now show that IGFBP-5 interacts with nuclear vitamin D receptor (VDR) and blocks retinoid X receptor (RXR):VDR heterodimerization. VDR and IGFBP-5 were shown to colocalize to the nuclei of MG-63 and U2-OS cells and coimmunoprecipitate in nuclear extracts from these cells. Induction of osteocalcin promoter activity and alkaline phosphatase activity by 1,25(OH)2D3 were significantly enhanced when IGFBP-5 was down-regulated in U2-OS cells. Moreover, we found IGFBP-5 increased basal alkaline phosphatase activity and collagen α1 type 1 expression, and that 1,25(OH)2D3 was unable to further induce the expression of these bone differentiation markers in MG-63 cells. Expression of IGFBP-5 inhibited MG-63 cell growth and caused cell cycle arrest at G0/G1 and G2/M. Furthermore, IGFBP-5 reduced the effects of 1,25(OH)2D3 in blocking cell cycle progression at G0/G1 and decreased the expression of cyclin D1. These results demonstrate that IGFBP-5 can interact with VDR to prevent RXR:VDR heterodimerization and suggest that IGFBP-5 may attenuate the 1,25(OH)2D3-induced expression of bone differentiation markers while having a modest effect on the 1,25(OH)2D3-mediated inhibition of cell cycle progression in bone cells.

scholarly journals A New Method for Chromosomes Preparation by ATP-Competitive Inhibitor SP600125 via Enhancement of Endomitosis in Fish

2021 ◽  
Vol 8 ◽  
Author(s):  
Wenting Xu ◽  
Yanxiu Mo ◽  
Yu He ◽  
Yunpeng Fan ◽  
Guomin He ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Spindle Assembly Checkpoint ◽  
Competitive Inhibitor ◽  
P53 Signaling ◽  
Cycle Arrest ◽  
Cultured Fish ◽  
Block Cell Cycle Progression ◽  
Fish Cells

Previous studies have suggested that 1,9-Pyrazoloanthrone, known as SP600125, can induce cell polyploidization. However, what is the phase of cell cycle arrest caused by SP600125 and the underlying regulation is still an interesting issue to be further addressed. Research in this article shows that SP600125 can block cell cycle progression at the prometaphase of mitosis and cause endomitosis. It is suggested that enhancement of the p53 signaling pathway and weakening of the spindle assembly checkpoint are associated with the SP600125-induced cell cycle arrest. Using preliminary SP600125 treatment, the samples of the cultured fish cells and the fish tissues display a great number of chromosome splitting phases. Summarily, SP600125 can provide a new protocol of chromosomes preparation for karyotype analysis owing to its interference with prometaphase of mitosis.

Jab1-siRNA Induces Cell Growth Inhibition and Cell Cycle Arrest in Gall Bladder Cancer Cells via Targeting Jab1 Signalosome

2020 ◽  
Vol 19 (16) ◽  
pp. 2019-2033 ◽  
Author(s):  
Pratibha Pandey ◽  
Mohammad H. Siddiqui ◽  
Anu Behari ◽  
Vinay K. Kapoor ◽  
Kumudesh Mishra ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
Cell Growth ◽  
Gall Bladder ◽  
Growth Inhibition ◽  
Cell Cycle Arrest ◽  
Gall Bladder Cancer ◽  
Cell Growth Inhibition ◽  
Cycle Arrest ◽  
Apoptotic Induction

Background: The aberrant alteration in Jab1 signalosome (COP9 Signalosome Complex Subunit 5) has been proven to be associated with the progression of several carcinomas. However the specific role and mechanism of action of Jab1 signalosome in carcinogenesis of gall bladder cancer (GBC) are poorly understood. Objective: The main objective of our study was to elucidate the role and mechanism of Jab1 signalosome in gall bladder cancer by employing siRNA. Methods: Jab1 overexpression was identified in gall bladder cancer tissue sample. The role of Jab1-siRNA approach in cell growth inhibition and apoptotic induction was then examined by RT-PCR, Western Blotting, MTT, ROS, Hoechst and FITC/Annexin-V staining. Results: In the current study, we have shown that overexpression of Jab1 stimulated the proliferation of GBC cells; whereas downregulation of Jab1 by using Jab1-siRNA approach resulted incell growth inhibition and apoptotic induction. Furthermore, we found that downregulation of Jab1 induces cell cycle arrest at G1 phase and upregulated the expression of p27, p53 and Bax gene. Moreover, Jab1-siRNA induces apoptosis by enhancing ROS generation and caspase-3 activation. In addition, combined treatment with Jab1-siRNA and gemicitabine demonstrated an enhanced decline in cell proliferation which further suggested increased efficacy of gemcitabine at a very lower dose (5μM) in combination with Jab1-siRNA. Conclusion: In conclusion, our study strongly suggests that targeting Jab1 signalosome could be a promising therapeutic target for the treatment of gall bladder cancer.

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