Functional differences between Hsp105/110 family proteins in cell proliferation, cell division, and drug sensitivity

AbstractDuring the mammalian preimplantation phase, cells undergo two subsequent cell fate decisions. During the first decision, the trophectoderm and the inner cell mass are formed. Subsequently, the inner cell mass segregates into the epiblast and the primitive endoderm. Inner cell mass organoids represent an experimental model system, mimicking the second cell fate decision. It has been shown that cells of the same fate tend to cluster stronger than expected for random cell fate decisions. Three major processes are hypothesised to contribute to the cell fate arrangements: (1) chemical signalling; (2) cell sorting; and (3) cell proliferation. In order to quantify the influence of cell proliferation on the observed cell lineage type clustering, we developed an agent-based model accounting for mechanical cell–cell interaction, i.e. adhesion and repulsion, cell division, stochastic cell fate decision and cell fate heredity. The model supports the hypothesis that initial cell fate acquisition is a stochastically driven process, taking place in the early development of inner cell mass organoids. Further, we show that the observed neighbourhood structures can emerge solely due to cell fate heredity during cell division.

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A possible relation between dietary zinc and cAMP in the regulation of tumour cell proliferation in the rat

British Journal Of Nutrition ◽

10.1079/bjn19880052 ◽

1988 ◽

Vol 59 (3) ◽

pp. 437-442 ◽

Cited By ~ 1

Author(s):

Noel S. Skeef ◽

John R. Duncan

Keyword(s):

Cell Proliferation ◽

Cell Division ◽

Cell Line ◽

Tumour Cell ◽

Tumour Growth ◽

Zn Deficiency ◽

Regenerating Liver ◽

Small Reduction ◽

Dietary Zinc ◽

Camp Concentration

1. The possibility of an effect of zinc on the rate of tumour cell division, mediated through a regulation of cellular cAMP concentration, was investigated in the present study in rats.2. Dietary Zn deficiency (< 1·5 mg Zn/kg) but not Zn excess (500 mg Zn/kg) resulted in an increased cAMP concentration in transplanted hepatoma cells. Neither treatment had any effect on the cAMP concentration in regenerating liver or normal resting liver. Both the deficient and excess Zn diets resulted in a small reduction in tumour growth (not statistically significant).3. The results seem to indicate that the relation investigated in the present study does not apply in the cell line used.

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Role of Cell Division Autoantigen 1 (CDA1) in Cell Proliferation and Fibrosis

Genes ◽

10.3390/genes1030335 ◽

2010 ◽

Vol 1 (3) ◽

pp. 335-348 ◽

Cited By ~ 3

Author(s):

Ban-Hock Toh ◽

Yugang Tu ◽

Zemin Cao ◽

Mark E. Cooper ◽

Zhonglin Chai

Keyword(s):

Cell Proliferation ◽

Cell Division

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HOXA11 Regulates Chemoresistance By Modulating p53 Gene Expression in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-127542 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5182-5182

Author(s):

Xutao Guo ◽

Bowen Yan ◽

Yi Qiu

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

Myeloid Leukemia ◽

Drug Sensitivity ◽

P53 Gene ◽

Resistant Cell ◽

Wild Type ◽

P53 Expression ◽

Acute Myeloid ◽

Resistant Cells

Acute myeloid leukemia (AML) exhibits large intrinsic variation in drug responsiveness due to its inherent heterogeneity. Therefore, it is important to understand the resistant mechanism in order to improve the treatment. In our previously study, the OCI-AML2-resistant cell lines were established to resist cytarabine (Ara-C) in the concentration of 50 µM (OCI-AML2 R50). The RNA-seq results showed that many genes changed in the resistant cells compared to wild type OCI-AML2 cells. One of the most remarkably decreased gene in resistant cells was HOXA11 (Homeobox A11). It is the part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which regulates gene expression, morphogenesis, and differentiation. In this study, we have evaluated the importance of HOXA11 in AML chemoresistance. We found that knockdown of HOXA11 repressed the WT OCI-AML2 cell proliferation and increased the population of cells expressing CD123 and CD47 LSC (Leukemia stem cell) markers and enhanced the resistance to Ara-C in vitro, while overexpression of HOXA11 showed the reverse effect. These results support the idea that HOXA11 promotes drug sensitivity and apoptosis in AML. However, the result also showed that overexpression of HOXA11 repressed the OCI-AML2 R50 cell proliferation and enhanced the resistance. Therefore, HOXA11 plays opposite role in sensitive cells and resistant cells. We further investigated the mechanism for these effects. We found that knockdown of HOXA11 decreased the p53 gene expression and overexpression of HOXA11 increased the expression of p53 in OCI-AML2 and R50 cells. Further, in OCI-AML2 R50 cells p53 has a hotspot mutation in DNA binding site and studies have shown that p53 mutation enhance cancer cell survival and chemoresistance. Therefore, our study shows dual roles for HOXA11 in cell survival. In p53 wild type parental AML2 cells, HOXA11 induces wild type p53 expression to enhance drug sensitivity while in resistant cell, HOXA11 promotes mutant p53 expression and enhances the resistance of chemotherapy. Disclosures No relevant conflicts of interest to declare.

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Molecular mechanism of cytokinin-activated cell division in Arabidopsis

Science ◽

10.1126/science.abe2305 ◽

2021 ◽

Vol 371 (6536) ◽

pp. 1350-1355

Author(s):

Weibing Yang ◽

Sandra Cortijo ◽

Niklas Korsbo ◽

Pawel Roszak ◽

Katharina Schiessl ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Division ◽

Histidine Kinase ◽

Feedback Loop ◽

Apical Meristem ◽

Nuclear Accumulation ◽

Cytokinin Signaling ◽

Positive Feedback Loop ◽

Nuclear Shuttling ◽

Stimulate Cell Proliferation

Mitogens trigger cell division in animals. In plants, cytokinins, a group of phytohormones derived from adenine, stimulate cell proliferation. Cytokinin signaling is initiated by membrane-associated histidine kinase receptors and transduced through a phosphorelay system. We show that in the Arabidopsis shoot apical meristem (SAM), cytokinin regulates cell division by promoting nuclear shuttling of Myb-domain protein 3R4 (MYB3R4), a transcription factor that activates mitotic gene expression. Newly synthesized MYB3R4 protein resides predominantly in the cytoplasm. At the G2-to-M transition, rapid nuclear accumulation of MYB3R4—consistent with an associated transient peak in cytokinin concentration—feeds a positive feedback loop involving importins and initiates a transcriptional cascade that drives mitosis and cytokinesis. An engineered nuclear-restricted MYB3R4 mimics the cytokinin effects of enhanced cell proliferation and meristem growth.

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Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1

10.1101/2021.03.19.436208 ◽

2021 ◽

Author(s):

Rosemarie E. Gough ◽

Matthew C. Jones ◽

Thomas Zacharchenko ◽

Shimin Le ◽

Miao Yu ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Cell Adhesion ◽

Cell Division ◽

Mechanical Response ◽

Direct Interaction ◽

Cyclin Dependent Kinase ◽

Cell Cycle Regulator ◽

Direct Binding

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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Expression of engrailed during segmentation in grasshopper and crayfish

Development ◽

10.1242/dev.107.2.201 ◽

1989 ◽

Vol 107 (2) ◽

pp. 201-212 ◽

Cited By ~ 29

Author(s):

N.H. Patel ◽

T.B. Kornberg ◽

C.S. Goodman

Keyword(s):

Monoclonal Antibody ◽

Cell Proliferation ◽

Cell Division ◽

Embryonic Stage ◽

Germ Band ◽

Segmentation Genes ◽

Pair Rule ◽

Drosophila Embryos ◽

The Way

We have used a monoclonal antibody that recognizes engrailed proteins to compare the process of segmentation in grasshopper, crayfish, and Drosophila. Drosophila embryos rapidly generate metameres during an embryonic stage characterized by the absence of cell division. In contrast, many other arthropod embryos, such as those of more primitive insects and crustaceans, generate metameres gradually and sequentially, as cell proliferation causes caudal elongation. In all three organisms, the pattern of engrailed expression at the segmented germ band stage is similar, and the parasegments are the first metameres to form. Nevertheless, the way in which the engrailed pattern is generated differs and reflects the differences in how these organisms generate their metameres. These differences call into question what role homologues of the Drosophila pair-rule segmentation genes might play in other arthropods that generate metameres sequentially.

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Reduction of the rate of outgrowth, cell density, and cell division following removal of the apical ectodermal ridge of the chick limb-bud

Development ◽

10.1242/dev.40.1.1 ◽

1977 ◽

Vol 40 (1) ◽

pp. 1-21

Author(s):

Dennis Summerbell

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Cell Division ◽

Cell Density ◽

Apical Ectodermal Ridge ◽

Limb Bud ◽

Short Term ◽

Density Dependent ◽

Wing Bud

Removal of the apical ectodermal ridge causes a reduction in the rate of outgrowth of the wing-bud and the loss of distal parts. More specifically it causes a short-term increase in cell density and cell death and a decrease in the rate of cell proliferation. The evidence supports the hypothesis of density-dependent control of cell division and suggests that there may also be a mechanism regulating skeletal length at the time of differentiation. An informal model is presented to explain the observations.

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A Rapid Degradation of Calponin 2 Is Required for Cytokinesis

AJP Cell Physiology ◽

10.1152/ajpcell.00569.2020 ◽

2021 ◽

Author(s):

Airong Qian ◽

Tzu-Bou Hsieh ◽

M. Moazzem Hossain ◽

Jim J.-C. Lin ◽

J.-P. Jin

Keyword(s):

Cell Proliferation ◽

Cell Division ◽

Underlying Mechanism ◽

Fluorescent Imaging ◽

Hek293 Cells ◽

Computer Assisted ◽

Over Expression ◽

Dividing Cells ◽

Ubiquitin Proteasome ◽

Dynamic Image Analysis

Calponin 2 is an actin cytoskeleton-associated protein and plays a role in regulating cell motility-related functions such as phagocytosis, migration and division. We previously reported that the expression of calponin 2 inhibits the rate of cell proliferation. To investigate the underlying mechanism, our present study found that the levels of endogenous calponin 2 in NIH3T3 and HEK293 cells rapidly decreased prior to cell division characterized by an absence at the actin contractile ring. In cells lacking endogenous calponin 2, transfective expression of GFP-fusion calponin 2 inhibited cell proliferation similar to that of non-fusion calponin 2. Fluorescent imaging studies of mitotic cells indicated that a proper level of calponin 2 expression and effective degradation during cytokinesis are necessary for normal cell division. Computer-assisted dynamic image analysis of dividing cells revealed that over-expression of calponin 2 significantly affects motile and shape behaviors of cells only on the interval from the start of anaphase to the start of cytokinesis, i.e., the pre-cytokinesis phase, but not on the interval from the start of cytokinesis to 50% completion of cytokinesis. The pre-cytokinesis degradation of calponin 2 was attenuated by MG132 inhibition of the ubiquitin proteasome and inhibitor of protein kinase C (PKC), suggesting that PKC phosphorylation-triggered degradation of calponin 2 could determine the rate of cytokinesis. The novel role of calponin 2 in regulating the rate of cytokinesis may be targeted for therapeutic applications such as in an inhibition of malignant tumor growth.

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