Cell cycle progression of chronic lymphocytic leukemia cells is controlled by cyclin D2, cyclin D3, cyclin-dependent kinase (cdk) 4 and the cdk inhibitor p27

ABSTRACT The steroid hormone progesterone regulates proliferation and differentiation in the mammary gland and uterus by cell cycle phase-specific actions. In breast cancer cells the predominant effect of synthetic progestins is long-term growth inhibition and arrest in G1 phase. Progestin-mediated growth arrest of T-47D breast cancer cells was preceded by inhibition of cyclin D1-Cdk4, cyclin D3-Cdk4, and cyclin E-Cdk2 kinase activities in vitro and reduced phosphorylation of pRB and p107. This was accompanied by decreases in the expression of cyclins D1, D3, and E, decreased abundance of cyclin D1- and cyclin D3-Cdk4 complexes, increased association of the cyclin-dependent kinase (CDK) inhibitor p27 with the remaining Cdk4 complexes, and changes in the molecular masses and compositions of cyclin E complexes. In control cells cyclin E eluted from Superdex 200 as two peaks of ∼120 and ∼200 kDa, with the 120-kDa peak displaying greater cyclin E-associated kinase activity. Following progestin treatment, almost all of the cyclin E was in the 200-kDa, low-activity form, which was associated with the CDK inhibitors p21 and p27; this change preceded the inhibition of cell cycle progression. These data suggest preferential formation of this higher-molecular-weight, CDK inhibitor-bound form and a reduced number of cyclin E-Cdk2 complexes as mechanisms for the decreased cyclin E-associated kinase activity following progestin treatment. Ectopic expression of cyclin D1 in progestin-inhibited cells led to the reappearance of the 120-kDa active form of cyclin E-Cdk2 preceding the resumption of cell cycle progression. Thus, decreased cyclin expression and consequent increased CDK inhibitor association are likely to mediate the decreases in CDK activity accompanying progestin-mediated growth inhibition.

Download Full-text

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.

Download Full-text

Alsterpaullone, a Cyclin-Dependent Kinase Inhibitor, Mediated Toxicity in HeLa Cells through Apoptosis-Inducing Effect

Journal of Analytical Methods in Chemistry ◽

10.1155/2013/602091 ◽

2013 ◽

Vol 2013 ◽

pp. 1-5 ◽

Cited By ~ 2

Author(s):

Chunying Cui ◽

Yuji Wang ◽

Yaonan Wang ◽

Ming Zhao ◽

Shiqi Peng

Keyword(s):

Cell Cycle ◽

Hela Cells ◽

Cell Cycle Progression ◽

Caspase 3 ◽

Kinase Inhibitor ◽

Cdk Inhibitor ◽

Cyclin Dependent Kinase ◽

Cycle Progression ◽

Cyclin Dependent Kinase Inhibitor ◽

Dose Dependent

Alsterpaullone, a small molecule cyclin-dependent kinase (CDK) inhibitor, regulates the cell cycle progression. Beyond death-inducing properties, we identified the effect of alsterpaullone on cycle procedure and apoptosis of HeLa cell. It was found that alsterpaullone inhibited HeLa cells in a time-dependent (0–72 h) and dose-dependent (0–30 μM) manner. In the presence of alsterpaullone, HeLa cells were arrested in G2/M prior to undergoing apoptosis via a mechanism that is involved in the regulation of various antiapoptotic genes, DNA-repair, transcription, and cell cycle progression. Compared to controls, alsterpaullone effectively prevented HeLa cells from entering S-phase. These potential therapeutic efficacies could be correlated with the activation of caspase-3.

Download Full-text

Timing of apoptosis onset depends on cell cycle progression in peripheral blood lymphocytes and lymphocytic leukemia cells

Oncology Reports ◽

10.3892/or.17.6.1437 ◽

2007 ◽

Cited By ~ 1

Author(s):

Yongdong Feng ◽

Jianhong Wu ◽

Xiaolan Feng ◽

Deding Tao ◽

Junbo Hu ◽

...

Keyword(s):

Cell Cycle ◽

Peripheral Blood ◽

Cell Cycle Progression ◽

Peripheral Blood Lymphocytes ◽

Lymphocytic Leukemia ◽

Leukemia Cells ◽

Cycle Progression ◽

Blood Lymphocytes

Download Full-text

Action of resveratrol alone or in combination with roscovitine, a CDK inhibitor, on cell cycle progression in human HL-60 leukemia cells

Biochemical Pharmacology ◽

10.1016/j.bcp.2008.08.002 ◽

2008 ◽

Vol 76 (11) ◽

pp. 1554-1562 ◽

Cited By ~ 14

Author(s):

Oxana Komina ◽

Józefa Węsierska-Gądek

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Leukemia Cells ◽

Cdk Inhibitor ◽

Cycle Progression

Download Full-text

AKT1 induces caspase-mediated cleavage of the CDK inhibitor p27Kip1 during cell cycle progression in leukemia cells transformed by FLT3-ITD

Leukemia Research ◽

10.1016/j.leukres.2011.09.006 ◽

2012 ◽

Vol 36 (2) ◽

pp. 205-211 ◽

Cited By ~ 3

Author(s):

Xinping Yang ◽

Suiyang Liu ◽

Surender Kharbanda ◽

Richard M. Stone

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Leukemia Cells ◽

Cdk Inhibitor ◽

Cycle Progression

Download Full-text

Budding yeast relies on G1 cyclin specificity to couple cell cycle progression with morphogenetic development

Science Advances ◽

10.1126/sciadv.abg0007 ◽

2021 ◽

Vol 7 (23) ◽

pp. eabg0007

Author(s):

Deniz Pirincci Ercan ◽

Florine Chrétien ◽

Probir Chakravarty ◽

Helen R. Flynn ◽

Ambrosius P. Snijders ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Budding Yeast ◽

Quantitative Model ◽

Cyclin Dependent Kinase ◽

Cycle Progression ◽

Model Cell ◽

Mitotic Cyclin ◽

Substrate Phosphorylation ◽

The Cost

Two models have been put forward for cyclin-dependent kinase (Cdk) control of the cell cycle. In the qualitative model, cell cycle events are ordered by distinct substrate specificities of successive cyclin waves. Alternatively, in the quantitative model, the gradual rise of Cdk activity from G1 phase to mitosis leads to ordered substrate phosphorylation at sequential thresholds. Here, we study the relative contributions of qualitative and quantitative Cdk control in Saccharomyces cerevisiae. All S phase and mitotic cyclins can be replaced by a single mitotic cyclin, albeit at the cost of reduced fitness. A single cyclin can also replace all G1 cyclins to support ordered cell cycle progression, fulfilling key predictions of the quantitative model. However, single-cyclin cells fail to polarize or grow buds and thus cannot survive. Our results suggest that budding yeast has become dependent on G1 cyclin specificity to couple cell cycle progression to essential morphogenetic events.

Download Full-text

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

Journal of Experimental Medicine ◽

10.1084/jem.20120800 ◽

2012 ◽

Vol 209 (12) ◽

pp. 2199-2213 ◽

Cited By ~ 25

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.

Download Full-text