Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27

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.

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

Oncogene ◽

10.1038/onc.2008.174 ◽

2008 ◽

Vol 27 (42) ◽

pp. 5635-5642 ◽

Cited By ~ 33

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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The critical role of cyclin D2 in cell cycle progression and tumorigenicity of glioblastoma stem cells

Oncogene ◽

10.1038/onc.2012.399 ◽

2012 ◽

Vol 32 (33) ◽

pp. 3840-3845 ◽

Cited By ~ 34

Author(s):

R Koyama-Nasu ◽

Y Nasu-Nishimura ◽

T Todo ◽

Y Ino ◽

N Saito ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Cell Cycle Progression ◽

Critical Role ◽

Cyclin D2 ◽

Cycle Progression ◽

Glioblastoma Stem Cells

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Increased Expression of Cyclin D2 during Multiple States of Growth Arrest in Primary and Established Cells

Molecular and Cellular Biology ◽

10.1128/mcb.18.6.3163 ◽

1998 ◽

Vol 18 (6) ◽

pp. 3163-3172 ◽

Cited By ~ 79

Author(s):

Muthupalaniappan Meyyappan ◽

Howard Wong ◽

Christopher Hull ◽

Karl T. Riabowol

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Growth Arrest ◽

Growth Conditions ◽

Cellular Growth ◽

Serum Starvation ◽

Cyclin D2 ◽

Cycle Progression ◽

Quiescent Cells ◽

D2 Protein

ABSTRACT Cyclin D2 is a member of the family of D-type cyclins that is implicated in cell cycle regulation, differentiation, and oncogenic transformation. To better understand the role of this cyclin in the control of cell proliferation, cyclin D2 expression was monitored under various growth conditions in primary human and established murine fibroblasts. In different states of cellular growth arrest initiated by contact inhibition, serum starvation, or cellular senescence, marked increases (5- to 20-fold) were seen in the expression levels of cyclin D2 mRNA and protein. Indirect immunofluorescence studies showed that cyclin D2 protein localized to the nucleus in G0, suggesting a nuclear function for cyclin D2 in quiescent cells. Cyclin D2 was also found to be associated with the cyclin-dependent kinases CDK2 and CDK4 but not CDK6 during growth arrest. Cyclin D2-CDK2 complexes increased in amounts but were inactive as histone H1 kinases in quiescent cells. Transient transfection and needle microinjection of cyclin D2 expression constructs demonstrated that overexpression of cyclin D2 protein efficiently inhibited cell cycle progression and DNA synthesis. These data suggest that in addition to a role in promoting cell cycle progression through phosphorylation of retinoblastoma family proteins in some cell systems, cyclin D2 may contribute to the induction and/or maintenance of a nonproliferative state, possibly through sequestration of the CDK2 catalytic subunit.

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

Molecular and Cellular Biology ◽

10.1128/mcb.21.18.6346-6357.2001 ◽

2001 ◽

Vol 21 (18) ◽

pp. 6346-6357 ◽

Cited By ~ 39

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.

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