Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E

AbstractTalin is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behaviour of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronised phosphorylation of a large number of protein targets. CDK1 activity also maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesiveness that are required for successful completion of mitosis. Using a combination of biochemical, structural and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8 through the use of recombinant fragments. Talin also contains a consensus CDK1 phosphorylation motif centred on S1589; a site that was phosphorylated by CDK1in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of KANK and weakened the mechanical response of the region, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator, CDK1, to the primary integrin effector, talin, therefore provides a primordial solution for coupling the cell proliferation and cell adhesion machineries, and thereby enables microenvironmental control of cell division in multicellular organisms.SummaryThe direct binding of the master cell cycle regulator, CDK1, to the primary integrin effector, talin, provides a primordial solution for coupling the cell proliferation and cell adhesion machineries, and thereby enables microenvironmental control of cell division.

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Mad1 Function in Cell Proliferation and Transcriptional Repression Is Antagonized by Cyclin E/CDK2

Journal of Biological Chemistry ◽

10.1074/jbc.c400611200 ◽

2005 ◽

Vol 280 (16) ◽

pp. 15489-15492 ◽

Cited By ~ 15

Author(s):

Sabine Rottmann ◽

Annette R. Menkel ◽

Caroline Bouchard ◽

Jürgen Mertsching ◽

Peter Loidl ◽

...

Keyword(s):

Phase Transition ◽

Cell Proliferation ◽

Transcriptional Repression ◽

Cyclin E ◽

S Phase ◽

Cellular Behavior ◽

Corepressor Complex ◽

Repressor Complex ◽

Phase Progression ◽

Cell Cycle Regulator Cyclin

The transcription factors of the Myc/Max/Mad network play essential roles in the regulation of cellular behavior. Mad1 inhibits cell proliferation by recruiting an mSin3-corepressor complex that contains histone deacetylase activity. Here we demonstrate that Mad1 is a potent inhibitor of the G1to S phase transition, a function that requires Mad1 to heterodimerize with Max and to bind to the corepressor complex. Cyclin E/CDK2, but not cyclin D and cyclin A complexes, fully restored S phase progression. In addition inhibition of colony formation and gene repression by Mad1 were also efficiently antagonized by cyclin E/CDK2. This was the result of cyclin E/CDK2 interfering with the interaction of Mad1 with HDAC1 and reducing HDAC activity. Our findings define a novel interplay between the cell cycle regulator cyclin E/CDK2 and Mad1 and its associated repressor complex and suggests an additional mechanism how cyclin E/CDK2 affects the G1to S phase transition.

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Real time detection of cell cycle regulator cyclin A on living tumor cells with europium emission

Dalton Transactions ◽

10.1039/c3dt51053k ◽

2013 ◽

Vol 42 (37) ◽

pp. 13495 ◽

Cited By ~ 4

Author(s):

Hongguang Li ◽

Frances L. Chadbourne ◽

Rongfeng Lan ◽

Chi-Fai Chan ◽

Wai-Lun Chan ◽

...

Keyword(s):

Cell Cycle ◽

Real Time ◽

Tumor Cells ◽

Cyclin A ◽

Cell Cycle Regulator ◽

Real Time Detection ◽

Cell Cycle Regulator Cyclin

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DEC1 regulates breast cancer cell proliferation by stabilizing cyclin E protein and delays the progression of cell cycle S phase

Cell Death and Disease ◽

10.1038/cddis.2015.247 ◽

2015 ◽

Vol 6 (9) ◽

pp. e1891-e1891 ◽

Cited By ~ 24

Author(s):

H Bi ◽

S Li ◽

X Qu ◽

M Wang ◽

X Bai ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cyclin E ◽

S Phase ◽

Cancer Cell Proliferation ◽

Breast Cancer Cell Proliferation ◽

E Protein

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Cell proliferation and differentiation in mouse developing suture based on cell cycle regulator localization.

Ensho Saisei ◽

10.2492/jsir.23.29 ◽

2003 ◽

Vol 23 (1) ◽

pp. 29-33

Author(s):

Sachiko Iseki ◽

Eishi Takahashi

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Cell Cycle Regulator ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation

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

The American Journal of Chinese Medicine ◽

10.1142/s0192415x03001260 ◽

2003 ◽

Vol 31 (04) ◽

pp. 563-572 ◽

Cited By ~ 3

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.

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Inhibition of Human Umbilical Vein Endothelial Cell Proliferation by the CXC Chemokine, Platelet Factor 4 (PF4), Is Associated With Impaired Downregulation of p21Cip1/WAF1

Blood ◽

10.1182/blood.v93.1.25.401a47_25_33 ◽

1999 ◽

Vol 93 (1) ◽

pp. 25-33 ◽

Cited By ~ 1

Author(s):

Grazia Gentilini ◽

Nancy E. Kirschbaum ◽

James A. Augustine ◽

Richard H. Aster ◽

Gian Paolo Visentin

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Endothelial Cell ◽

Umbilical Vein ◽

Cyclin E ◽

Endothelial Cell Proliferation ◽

Cyclin Dependent Kinase ◽

Platelet Factor ◽

Human Umbilical Vein ◽

Cdk2 Activity

Human PF4 is a heparin-binding chemokine known to be capable of inhibiting endothelial cell proliferation and angiogenesis. To explore the biological mechanisms responsible for this action, we investigated the effect of PF4 on epidermal growth factor (EGF)-stimulated human umbilical vein endothelial cells (HUVEC), a model system in which stimulation is essentially independent of interaction with cell-surface glycosaminoglycans. Based on previous findings that PF4 blocks endothelial cell cycle entry and progression into S phase, we studied the molecular mechanism(s) of PF4 interference with cell cycle machinery. PF4 treatment of EGF-stimulated HUVEC caused a decrease in cyclin E–cyclin-dependent kinase 2 (cdk2) activity with resulting attenuation of retinoblastoma protein phosphorylation. PF4-dependent downregulation of cyclin E-cdk2 activity was associated with increased binding of the cyclin-dependent kinase inhibitor, p21Cip1/WAF1, to the cyclin E-cdk2 complex. Analysis of total cellular p21Cip1/WAF1 showed that in the presence of PF4, p21Cip1/WAF1 levels were sustained at time points when p21Cip1/WAF1 was no longer detectable in cells stimulated by EGF in the absence of PF4. These findings indicate that PF4 inhibition of HUVEC proliferation in response to EGF is associated with impaired downregulation of p21Cip1/WAF1 and provide the first evidence for interference with cell cycle mechanisms by a chemokine.

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