scholarly journals Transgene Expression of bcl-xL Permits Anti-immunoglobulin (Ig)–induced Proliferation in xid B Cells

1998 ◽  
Vol 187 (7) ◽  
pp. 1081-1091 ◽  
Author(s):  
Nanette Solvason ◽  
Wei Wei Wu ◽  
Nisha Kabra ◽  
Fridjtof Lund-Johansen ◽  
Maria Grazia Roncarolo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
Transgene Expression ◽  
Cell Cycle Progression ◽  
Regulatory Protein ◽  
Ectopic Expression ◽  
Regulatory Proteins ◽  
High Rate ◽  
Cycle Progression ◽  
Cell Cycle Regulatory Proteins

Mutations in the tyrosine kinase, Btk, result in a mild immunodeficiency in mice (xid). While B lymphocytes from xid mice do not proliferate to anti-immunoglobulin (Ig), we show here induction of the complete complement of cell cycle regulatory molecules, though the level of induction is about half that detected in normal B cells. Cell cycle analysis reveals that anti-Ig stimulated xid B cells enter S phase, but fail to complete the cell cycle, exhibiting a high rate of apoptosis. This correlated with a decreased ability to induce the anti-apoptosis regulatory protein, Bcl-xL. Ectopic expression of Bcl-xL in xid B cells permitted anti-Ig induced cell cycle progression demonstrating dual requirements for induction of anti-apoptotic proteins plus cell cycle regulatory proteins during antigen receptor mediated proliferation. Furthermore, our results link one of the immunodeficient traits caused by mutant Btk with the failure to properly regulate Bcl-xL.

scholarly journals Promotion of Cell Cycle Progression by Basic Helix-Loop-Helix E2A

2001 ◽  
Vol 21 (18) ◽  
pp. 6346-6357 ◽  
Author(s):  
Fang Zhao ◽  
Antonina Vilardi ◽  
Robert J. Neely ◽  
John Kim Choi
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
B Cell ◽  
Cell Line ◽  
Cell Cycle Progression ◽  
Ectopic Expression ◽  
Cyclin D3 ◽  
Cyclin D2 ◽  
Cycle Progression ◽  
Fusion Construct

ABSTRACT Normal B-cell development requires the E2A gene and its encoded transcription factors E12 and E47. Current models predict that E2A promotes cell differentiation and inhibits G1 cell cycle progression. The latter raises the conundrum of how B cells proliferate while expressing high levels of E2A protein. To study the relationship between E2A and cell proliferation, we established a tissue culture-based model in which the activity of E2A can be modulated in an inducible manner using E47R, an E47-estrogen fusion construct, and E47ERT, a dominant negative E47-estrogen fusion construct. The two constructs were subcloned into retroviral vectors and expressed in the human pre-B-cell line 697, the human myeloid progenitor cell line K562, and the murine fibroblastic cell line NIH 3T3. In both B cells and non-B cells, suppression of E2A activity by E47ERT inhibited G1 progression and was associated with decreased expression of multiple cyclins including the G1-phase cyclin D2 and cyclin D3. Consistent with these findings, E2A null mice expressed decreased levels of cyclin D2 and cyclin D3 transcripts. In complementary experiments, ectopic expression of E47R promoted G1 progression and was associated with increased levels of multiple cyclins, including cyclin D2 and cyclin D3. The induction of some cyclin transcripts occurred even in the absence of protein synthesis. We conclude that, in some cells, E2A can promote cell cycle progression, contrary to the present view that E2A inhibits G1 progression.

Effects of Aqueous Extract of Sophora flavescens on the Expression of Cell Cycle Regulatory Proteins in Human Oral Mucosal Fibroblasts

2003 ◽  
Vol 31 (04) ◽  
pp. 563-572 ◽  
Author(s):  
Hyun-A Kim ◽  
Hyung-Keun You ◽  
Hyung-Shik Shin ◽  
Youn-Chul Kim ◽  
Tai-Hyun Kang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
Regulatory Proteins ◽  
Cyclin D ◽  
Sophora Flavescens ◽  
Cycle Progression ◽  
Cell Cycle Regulatory Proteins ◽  
Cycle Regulation

Sophorae Radix, the dried roots of Sophora flavescens AITON (Leguminosae), has been used in Oriental traditional medicine for treatment of skin and mucosal ulcers, sores, gastrointestinal hemorrhage, diarrhea, inflammation and arrhythmia. In the present study, we examine the effect of the aqueous extract of Sophorae Radix (AESR) on cell proliferation and cell cycle regulation in human oral mucosal fibroblasts (HOMFs). To study the molecular mechanisms of cell cycle regulation by AESR, we also measured the intracellular levels of cell cycle regulatory proteins such as cyclin D, cyclin-dependent kinases (CDK)-4, CDK-6, cyclin E, CDK-2, p53, p21WAF1/CIP1 and p16INK4 . Cell proliferation was increased in the presence of 10~500 μg/ml of AESR. Maximal growth stimulation was observed in those cells exposed to 100 μg/ml of AESR. Exposure of HOMFs to 100 μg/ml of AESR resulted in an increase of cell cycle progression. The levels of cyclin E and CDK-2 were increased in HOMFs after 100 μg/ml of AESR treatment, but the levels of cyclin D, CDK-4, and CDK-6 were unchanged. After exposure to 100 μg/ml of AESR, the protein levels of p16INK4A and p53 were decreased as compared to that of the control group, but the level of p21WAF1/CIP1 was similar in the cells treated with 100 μg/ml of AESR and untreated cells. The results suggest that AESR may increase cell proliferation and cell cycle progression in HOMFs, which is linked to increased cellular levels of cyclin E and CDK-2 and decreased cellular levels of p53 and p16INK4A . Further studies are necessary to clarify the active constituents of AESR responsible for such biomolecular activities.

scholarly journals The Rho GTPase Effector ROCK Regulates Cyclin A, Cyclin D1, and p27Kip1 Levels by Distinct Mechanisms

2006 ◽  
Vol 26 (12) ◽  
pp. 4612-4627 ◽  
Author(s):  
Daniel R. Croft ◽  
Michael F. Olson
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Rho Gtpase ◽  
Cyclin A ◽  
Regulatory Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Lim Kinase ◽  
Cycle Progression ◽  
Cell Cycle Regulatory Proteins

ABSTRACT The members of the Rho GTPase family are well known for their regulation of actin cytoskeletal structures. In addition, they influence progression through the cell cycle. The RhoA and RhoC proteins regulate numerous effector proteins, with a central and vital signaling role mediated by the ROCK I and ROCK II serine/threonine kinases. The requirement for ROCK function in the proliferation of numerous cell types has been revealed by studies utilizing ROCK-selective inhibitors such as Y-27632. However, the mechanisms by which ROCK signaling promotes cell cycle progression have not been thoroughly characterized. Using a conditionally activated ROCK-estrogen receptor fusion protein, we found that ROCK activation is sufficient to stimulate G1/S cell cycle progression in NIH 3T3 mouse fibroblasts. Further analysis revealed that ROCK acts via independent pathways to alter the levels of cell cycle regulatory proteins: cyclin D1 and p21Cip1 elevation via Ras and the mitogen-activated protein kinase pathway, increased cyclin A via LIM kinase 2, and reduction of p27Kip1 protein levels. Therefore, the influence of ROCK on cell cycle regulatory proteins occurs by multiple independent mechanisms.

scholarly journals p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells

2005 ◽  
Vol 153 (1) ◽  
pp. 123-133 ◽  
Author(s):  
C Corrèze ◽  
J-P Blondeau ◽  
M Pomérance
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
Regulatory Proteins ◽  
Thyroid Cells ◽  
Cycle Progression ◽  
Mapk Activity ◽  
Mitogen Activated Protein ◽  
Cell Cycle Regulatory Proteins ◽  
P38 Mapks

Objective: Thyrotropin activates the cAMP pathway in thyroid cells, and stimulates cell cycle progression in cooperation with insulin or insulin-like growth factor-I. Because p38 mitogen-activated protein kinases (p38 MAPKs) were stimulated by cAMP in the FRTL-5 rat thyroid cell line, we investigated (i) the effect of the specific inhibition of p38 MAPKs on FRTL-5 cell proliferation and (ii) the mechanism of action of p38 MAPKs on cell cycle control, by studying the expression and/or the activity of several cell cycle regulatory proteins in FRTL-5 cells. Methods: DNA synthesis was monitored by incorporation of [3H]thymidine into DNA and the cell cycle distribution was assessed by fluorescence-activated cell sorter analysis. Expression of cell cycle regulatory proteins was determined by Western blot analysis. Cyclin-dependent kinase 2 (Cdk2) activity associated to cyclin E was immunoprecipitated and was measured by an in vitro kinase assay. Results: SB203580, an inhibitor of α and β isoforms of p38 MAPKs, but not its inactive analog SB202474, inhibited DNA synthesis and the G1-S transition induced by forskolin plus insulin. SB203580 inhibited specifically p38 MAPK activity but not other kinase activities such as Akt and p70-S6 kinase. Treatment of FRTL-5 cells with SB203580 decreased total and cyclin E-associated Cdk2 kinase activity stimulated with forskolin and insulin. However, inhibition of p38 MAPKs by SB203580 was without effect on total cyclin E and Cdk2 levels. The decrease in Cdk2 kinase activity caused by SB203580 treatment was not due to an increased expression of p21Cip1 or p27Kip1 inhibitory proteins. In addition, SB203580 affected neither Cdc25A phosphatase expression nor Cdk2 Tyr-15 phosphorylation. Inhibition of p38 MAPKs decreased Cdk2-cyclin E activation by regulating the subcellular localization of Cdk2 and its phosphorylation on Thr-160. Conclusions: These results indicate that p38 MAPK activity is involved in the regulation of cell cycle progression in FRTL-5 thyroid cells, at least in part by increasing nuclear Cdk2 activity.

scholarly journals Cyclin E and Bcl-xL cooperatively induce cell cycle progression in c-Rel−/− B cells

Oncogene ◽  
2003 ◽  
Vol 22 (52) ◽  
pp. 8472-8486 ◽  
Author(s):  
Shuhua Cheng ◽  
Constance Yu Hsia ◽  
Gustavo Leone ◽  
Hsiou-Chi Liou
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
Cycle Progression ◽  
Induce Cell Cycle Progression

scholarly journals B Lymphocytes Differentially Use the Rel and Nuclear Factor κB1 (NF-κB1) Transcription Factors to Regulate Cell Cycle Progression and Apoptosis in Quiescent and Mitogen-activated Cells

1998 ◽  
Vol 187 (5) ◽  
pp. 663-674 ◽  
Author(s):  
Raelene J. Grumont ◽  
Ian J. Rourke ◽  
Lorraine A. O'Reilly ◽  
Andreas Strasser ◽  
Kensuke Miyake ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Transcription Factors ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Cycle Progression ◽  
Nuclear Factor ◽  
Cycle Progression ◽  
Regulate Cell Cycle Progression

Rel and nuclear factor (NF)-κB1, two members of the Rel/NF-κB transcription factor family, are essential for mitogen-induced B cell proliferation. Using mice with inactivated Rel or NF-κB1 genes, we show that these transcription factors differentially regulate cell cycle progression and apoptosis in B lymphocytes. Consistent with an increased rate of mature B cell turnover in naive nfkb1−/− mice, the level of apoptosis in cultures of quiescent nfkb1−/−, but not c-rel−/−, B cells is higher. The failure of c-rel−/− or nfkb1−/− B cells to proliferate in response to particular mitogens coincides with a cell cycle block early in G1 and elevated cell death. Expression of a bcl-2 transgene prevents apoptosis in resting and activated c-rel−/− and nfkb1−/− B cells, but does not overcome the block in cell cycle progression, suggesting that the impaired proliferation is not simply a consequence of apoptosis and that Rel/NF-κB proteins regulate cell survival and cell cycle control through independent mechanisms. In contrast to certain B lymphoma cell lines in which mitogen-induced cell death can result from Rel/NF-κB–dependent downregulation of c-myc, expression of c-myc is normal in resting and stimulated c-rel−/− B cells, indicating that target gene(s) regulated by Rel that are important for preventing apoptosis may differ in normal and immortalized B cells. Collectively, these results are the first to demonstrate that in normal B cells, NF-κB1 regulates survival of cells in G0, whereas mitogenic activation induced by distinct stimuli requires different Rel/NF-κB factors to control cell cycle progression and prevent apoptosis.

scholarly journals Bromodomain Protein Brd4 Binds to GTPase-Activating SPA-1, Modulating Its Activity and Subcellular Localization

2004 ◽  
Vol 24 (20) ◽  
pp. 9059-9069 ◽  
Author(s):  
Andrea Farina ◽  
Masakazu Hattori ◽  
Jun Qin ◽  
Yoshihiro Nakatani ◽  
Nagahiro Minato ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Subcellular Localization ◽  
Cell Cycle Progression ◽  
Ectopic Expression ◽  
Gtpase Activating Protein ◽  
Functional Importance ◽  
Cycle Progression ◽  
Proper Balance ◽  
Mammalian Protein ◽  
Normal Cell Cycle

ABSTRACT Brd4 is a mammalian protein that contains a double bromodomain. It binds to chromatin and regulates cell cycle progression at multiple stages. By immunopurification and mass spectrometry, we identified a Rap GTPase-activating protein (GAP), signal-induced proliferation-associated protein 1 (SPA-1), as a factor that interacts with Brd4. SPA-1 localizes to the cytoplasm and to a lesser degree in the nucleus, while Brd4 resides in the nucleus. Bifluorescence complementation revealed that Brd4 and SPA-1 interact with each other in the nucleus of living cells. Supporting the functional importance of the interaction, Brd4 enhanced Rap GAP activity of SPA-1. Furthermore ectopic expression of SPA-1 and Brd4 redirected subcellular localization of the partner and disrupted normal cell cycle progression. These effects were, however, reversed by coexpression of the two proteins, indicating that a proper balance between Brd4 and SPA-1 in G2 is required for cell division. This work reveals a novel link between Brd4 and a GTPase-dependent mitogenic signaling pathway.

scholarly journals VP16 targets an amino-terminal domain of HCF involved in cell cycle progression.

1997 ◽  
Vol 17 (10) ◽  
pp. 6139-6146 ◽  
Author(s):  
A C Wilson ◽  
R N Freiman ◽  
H Goto ◽  
T Nishimoto ◽  
W Herr
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Regulatory Protein ◽  
Proteolytic Processing ◽  
Early Gene ◽  
Temperature Sensitive ◽  
Interaction Domain ◽  
Cycle Progression ◽  
Amino Terminal

The herpes simplex virus (HSV) regulatory protein VP16 activates HSV immediate-early gene transcription through formation of a multiprotein-DNA complex on viral promoters that includes the preexisting nuclear proteins HCF and Oct-1. The HCF protein is a complex of amino- and carboxy-terminal polypeptides derived from a large (approximately 2,000-amino-acid) precursor by proteolytic processing. Here we show that a 361-residue amino-terminal region of HCF is sufficient to bind VP16, stabilize VP16-induced complex assembly with Oct-1 and DNA, and activate transcription in vivo. This VP16 interaction region contains six kelch-like repeats, a degenerate repeat motif that is likely to fold as a distinctive beta-propeller structure. The third HCF kelch repeat includes a proline residue (P134) that is mutated to serine in hamster tsBN67 cells, resulting in a temperature-sensitive defect in cell proliferation. This missense mutation also prevents direct association between HCF and VP16, suggesting that VP16 mimics a cellular factor required for cell proliferation. Rescue of the tsBN67 cell proliferation defect by HCF, however, requires both the VP16 interaction domain and an adjacent basic region, indicating that HCF utilizes multiple regions to promote cell cycle progression.

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