scholarly journals Subnuclear cyclin D3 compartments and the coordinated regulation of proliferation and immunoglobulin variable gene repression

2012 ◽  
Vol 209 (12) ◽  
pp. 2199-2213 ◽  
Author(s):  
Sarah E. Powers ◽  
Malay Mandal ◽  
Satoshi Matsuda ◽  
Ana V. Miletic ◽  
Matthew H. Cato ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Gene Segment ◽  
Cyclin D3 ◽  
Cyclin D2 ◽  
Cycle Progression ◽  
Nuclear Compartment ◽  
Regulation Of Proliferation ◽  
Variable Gene ◽  
V Gene ◽  
Phosphoinositide 3 Kinase

Ubiquitously expressed D-type cyclins are required for hematopoiesis but are dispensable in other cell lineages. Furthermore, within different hematopoietic progenitor populations the D-type cyclins play nonredundant roles. The basis of this lineage and developmental specificity is unknown. In pro–B cells we demonstrate four distinct nuclear D-type cyclin compartments, including one cyclin D3 fraction associated with CDK4 and another phosphoinositide 3-kinase–regulated fraction not required for proliferation. A third fraction of cyclin D3 was associated with the nuclear matrix and repression of >200 genes including the variable (V) gene segments Igkv1-117, Iglv1, and Igh-VJ558. Consistent with different subnuclear compartments and functions, distinct domains of cyclin D3 mediated proliferation and Igk V gene segment repression. None of the cyclin D3 nuclear compartments overlapped with cyclin D2, which was distributed, unbound to CDK4, throughout the nucleus. Furthermore, compartmentalization of the cyclins appeared to be lineage restricted because in fibroblasts, cyclin D2 and cyclin D3 occupied a single nuclear compartment and neither bound CDK4 efficiently. These data suggest that subnuclear compartmentalization enables cyclin D3 to drive cell cycle progression and repress V gene accessibility, thereby ensuring coordination of proliferation with immunoglobulin recombination.

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.

scholarly journals Distinct Cell Cycle Timing Requirements for Extracellular Signal-Regulated Kinase and Phosphoinositide 3-Kinase Signaling Pathways in Somatic Cell Mitosis

2002 ◽  
Vol 22 (20) ◽  
pp. 7226-7241 ◽  
Author(s):  
Elisabeth C. Roberts ◽  
Paul S. Shapiro ◽  
Theresa Stines Nahreini ◽  
Gilles Pages ◽  
Jacques Pouyssegur ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cyclin B1 ◽  
Erk Pathway ◽  
Cycle Progression ◽  
Mitotic Entry ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Phosphoinositide 3 Kinase ◽  
And Function

ABSTRACT Mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K) pathways are necessary for cell cycle progression into S phase; however the importance of these pathways after the restriction point is poorly understood. In this study, we examined the regulation and function of extracellular signal-regulated kinase (ERK) and PI3K during G2/M in synchronized HeLa and NIH 3T3 cells. Phosphorylation and activation of both the MAP kinase kinase/ERK and PI3K/Akt pathways occur in late S and persist until the end of mitosis. Signaling was rapidly reversed by cell-permeable inhibitors, indicating that both pathways are continuously activated and rapidly cycle between active and inactive states during G2/M. The serum-dependent behavior of PI3K/Akt versus ERK pathway activation indicates that their mechanisms of regulation differ during G2/M. Effects of cell-permeable inhibitors and dominant-negative mutants show that both pathways are needed for mitotic progression. However, inhibiting the PI3K pathway interferes with cdc2 activation, cyclin B1 expression, and mitotic entry, whereas inhibiting the ERK pathway interferes with mitotic entry but has little effect on cdc2 activation and cyclin B1 and retards progression from metaphase to anaphase. Thus, our study provides novel evidence that ERK and PI3K pathways both promote cell cycle progression during G2/M but have different regulatory mechanisms and function at distinct times.

scholarly journals Fbxl8 suppresses lymphoma growth and hematopoietic transformation through degradation of cyclin D3

Oncogene ◽  
2020 ◽  
Author(s):  
Akihiro Yoshida ◽  
Jaewoo Choi ◽  
Hong Ri Jin ◽  
Yan Li ◽  
Sagar Bajpai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Human Cancer ◽  
E3 Ligase ◽  
Protein Stabilization ◽  
Cyclin D3 ◽  
Deficient Mutant ◽  
Cycle Progression ◽  
Functional Investigation

Abstract Overexpression of D-type cyclins in human cancer frequently occurs as a result of protein stabilization, emphasizing the importance of identification of the machinery that regulates their ubiqutin-dependent degradation. Cyclin D3 is overexpressed in ~50% of Burkitt’s lymphoma correlating with a mutation of Thr-283. However, the E3 ligase that regulates phosphorylated cyclin D3 and whether a stabilized, phosphorylation deficient mutant of cyclin D3, has oncogenic activity are undefined. We describe the identification of SCF-Fbxl8 as the E3 ligase for Thr-283 phosphorylated cyclin D3. SCF-Fbxl8 poly-ubiquitylates p-Thr-283 cyclin D3 targeting it to the proteasome. Functional investigation demonstrates that Fbxl8 antagonizes cell cycle progression, hematopoietic cell proliferation, and oncogene-induced transformation through degradation of cyclin D3, which is abolished by expression of cyclin D3T283A, a non-phosphorylatable mutant. Clinically, the expression of cyclin D3 is inversely correlated with the expression of Fbxl8 in lymphomas from human patients implicating Fbxl8 functions as a tumor suppressor.

scholarly journals The N-Terminal 24 Amino Acids of the p55 Gamma Regulatory Subunit of Phosphoinositide 3-Kinase Binds Rb and Induces Cell Cycle Arrest

2003 ◽  
Vol 23 (5) ◽  
pp. 1717-1725 ◽  
Author(s):  
Xianmin Xia ◽  
Aiwu Cheng ◽  
Damilola Akinmade ◽  
Anne W. Hamburger
Keyword(s):  
Cell Cycle ◽  
Amino Acid ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Biological Effects ◽  
Cycle Progression ◽  
Regulatory Subunits ◽  
Cycle Arrest ◽  
Phosphoinositide 3 Kinase

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.

scholarly journals EPO modulation of cell-cycle regulatory genes, and cell division, in primary bone marrow erythroblasts

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2361-2370 ◽  
Author(s):  
Jing Fang ◽  
Madhu Menon ◽  
William Kapelle ◽  
Olga Bogacheva ◽  
Oleg Bogachev ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Regulatory Genes ◽  
Primary System ◽  
Cyclin D2 ◽  
Cycle Progression ◽  
Cyclin G2 ◽  
Cell Cycle Regulatory Genes

Erythropoietin (EPO's) actions on erythroblasts are ascribed largely to survival effects. Certain studies, however, point to EPO-regulated proliferation. To investigate this problem in a primary system, KitposCD71high erythroblasts were prepared from murine bone marrow, and were first used in the array-based discovery of EPO-modulated cell-cycle regulators. Five cell-cycle progression factors were rapidly up-modulated: nuclear protein 1 (Nupr1), G1 to S phase transition 1 (Gspt1), early growth response 1 (Egr1), Ngfi-A binding protein 2 (Nab2), and cyclin D2. In contrast, inhibitory cyclin G2, p27/Cdkn1b, and B-cell leukemia/lymphoma 6 (Bcl6) were sharply down-modulated. For CYCLIN G2, ectopic expression also proved to selectively attenuate EPO-dependent UT7epo cell-cycle progression at S-phase. As analyzed in primary erythroblasts expressing minimal EPO receptor alleles, EPO repression of cyclin G2 and Bcl6, and induction of cyclin D2, were determined to depend on PY343 (and Stat5) signals. Furthermore, erythroblasts expressing a on PY-null EPOR-HM allele were abnormally distributed in G0/G1. During differentiation divisions, EPOR-HM Ter119pos erythroblasts conversely accumulated in S-phase and faltered in an apparent EPO-directed transition to G0/G1. EPO/EPOR signals therefore control the expression of select cell-cycle regulatory genes that are proposed to modulate stage-specific decisions for erythroblast cell-cycle progression.

scholarly journals Subnuclear cyclin D3 compartments and the coordinated regulation of proliferation and immunoglobulin variable gene repression

2012 ◽  
Vol 199 (4) ◽  
pp. i4-i4
Author(s):  
Sarah E. Powers ◽  
Malay Mandal ◽  
Satoshi Matsuda ◽  
Ana V. Miletic ◽  
Matthew H. Cato ◽  
...  
Keyword(s):  
Cyclin D3 ◽  
Gene Repression ◽  
Regulation Of Proliferation ◽  
Variable Gene ◽  
Coordinated Regulation

scholarly journals Activation of the cyclin D2 and cdk6 genes through NF-κB is critical for cell-cycle progression induced by HTLV-I Tax

Oncogene ◽  
2008 ◽  
Vol 27 (42) ◽  
pp. 5635-5642 ◽  
Author(s):  
R Iwanaga ◽  
E Ozono ◽  
J Fujisawa ◽  
M A Ikeda ◽  
N Okamura ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cyclin D2 ◽  
Cycle Progression
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