PDGF-PDGFR network differentially regulates, myogenic cell fate, migration, proliferation, and cell cycle progression

Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-x L by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies.

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Excess histone H3 is a Chk1 inhibitor that controls embryonic cell cycle progression

10.1101/2020.06.09.142414 ◽

2020 ◽

Author(s):

Yuki Shindo ◽

Amanda A. Amodeo

Keyword(s):

Cell Cycle ◽

Cell Fate ◽

Cell Cycle Progression ◽

Histone H3 ◽

Embryonic Cell ◽

Cycle Progression ◽

Cell Cycles ◽

Embryonic Cell Cycle

AbstractThe early embryos of many species undergo a switch from rapid, reductive cleavage divisions to slower, cell fate-specific division patterns at the Mid-Blastula Transition (MBT). The maternally loaded histone pool is used to measure the increasing ratio of nuclei to cytoplasm (N/C ratio) to control MBT onset, but the molecular mechanism of how histones regulate the cell cycle has remained elusive. Here, we show that excess histone H3 inhibits the DNA damage checkpoint kinase Chk1 to promote cell cycle progression in the Drosophila embryo. We find that excess H3-tail that cannot be incorporated into chromatin is sufficient to shorten the embryonic cell cycle and reduce the activity of Chk1 in vitro and in vivo. Removal of the Chk1 phosphosite in H3 abolishes its ability to regulate the cell cycle. Mathematical modeling quantitatively supports a mechanism where changes in H3 nuclear concentrations over the final cell cycles leading up to the MBT regulate Chk1-dependent cell cycle slowing. We provide a novel mechanism for Chk1 regulation by H3, which is crucial for proper cell cycle remodeling during early embryogenesis.

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Let-7 regulates cell cycle dynamics in the developing cerebral cortex and retina

Scientific Reports ◽

10.1038/s41598-019-51703-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Corinne L. A. Fairchild ◽

Simranjeet K. Cheema ◽

Joanna Wong ◽

Keiko Hino ◽

Sergi Simó ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Cell Fate ◽

Cell Cycle Progression ◽

Developmental Time ◽

Neural Progenitors ◽

Cycle Progression ◽

Cell Fate Decisions ◽

Cell Cycle Dynamics

Abstract In the neural progenitors of the developing central nervous system (CNS), cell proliferation is tightly controlled and coordinated with cell fate decisions. Progenitors divide rapidly during early development and their cell cycle lengthens progressively as development advances to eventually give rise to a tissue of the correct size and cellular composition. However, our understanding of the molecules linking cell cycle progression to developmental time is incomplete. Here, we show that the microRNA (miRNA) let-7 accumulates in neural progenitors over time throughout the developing CNS. Intriguingly, we find that the level and activity of let-7 oscillate as neural progenitors progress through the cell cycle by in situ hybridization and fluorescent miRNA sensor analyses. We also show that let-7 mediates cell cycle dynamics: increasing the level of let-7 promotes cell cycle exit and lengthens the S/G2 phase of the cell cycle, while let-7 knock down shortens the cell cycle in neural progenitors. Together, our findings suggest that let-7 may link cell proliferation to developmental time and regulate the progressive cell cycle lengthening that occurs during development.

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Life after meiosis: patterning the angiosperm male gametophyte

Biochemical Society Transactions ◽

10.1042/bst0380577 ◽

2010 ◽

Vol 38 (2) ◽

pp. 577-582 ◽

Cited By ~ 22

Author(s):

Michael Borg ◽

David Twell

Keyword(s):

Cell Cycle ◽

Cell Fate ◽

Cell Cycle Progression ◽

Male Gametophyte ◽

Cell Fate Determination ◽

Double Fertilization ◽

Cycle Progression ◽

Fate Determination ◽

Male Gametogenesis ◽

The Impact

Pollen grains represent the highly reduced haploid male gametophyte generation in angiosperms. They play an essential role in plant fertility by generating and delivering twin sperm cells to the embryo sac to undergo double fertilization. The functional specialization of the male gametophyte and double fertilization are considered to be key innovations in the evolutionary success of angiosperms. The haploid nature of the male gametophyte and its highly tractable ontogeny makes it an attractive system to study many fundamental biological processes, such as cell fate determination, cell-cycle progression and gene regulation. The present mini-review encompasses key advances in our understanding of the molecular mechanisms controlling male gametophyte patterning in angiosperms. A brief overview of male gametophyte development is presented, followed by a discussion of the genes required at landmark events of male gametogenesis. The value of the male gametophyte as an experimental system to study the interplay between cell fate determination and cell-cycle progression is also discussed and exemplified with an emerging model outlining the regulatory networks that distinguish the fate of the male germline from its sister vegetative cell. We conclude with a perspective of the impact emerging data will have on future research strategies and how they will develop further our understanding of male gametogenesis and plant development.

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Growth Factor Regulation of Cell Cycle Progression and Cell Fate Determination

Current Topics in Microbiology and Immunology - Mechanisms in B-Cell Neoplasia 1994 ◽

10.1007/978-3-642-79275-5_34 ◽

1995 ◽

pp. 291-303 ◽

Cited By ~ 3

Author(s):

Thomas W. Beck ◽

Nancy S. Magnuson ◽

Ulf R. Rapp

Keyword(s):

Cell Cycle ◽

Growth Factor ◽

Cell Fate ◽

Cell Cycle Progression ◽

Cell Fate Determination ◽

Cycle Progression ◽

Fate Determination ◽

Regulation Of Cell Cycle ◽

Growth Factor Regulation

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Advanced Single Cell Imaging Method Using Microfluidics and FUCCI to Determine Cell Cycle Progression and Cell Fate Decisions

Proceedings of the 2019 9th International Conference on Biomedical Engineering and Technology - ICBET' 19 ◽

10.1145/3326172.3326178 ◽

2019 ◽

Author(s):

Ming Xi Jiang ◽

Weichao Zhai

Keyword(s):

Cell Cycle ◽

Single Cell ◽

Cell Fate ◽

Cell Cycle Progression ◽

Cell Imaging ◽

Imaging Method ◽

Cycle Progression ◽

Cell Fate Decisions ◽

Single Cell Imaging

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Repressed synthesis of ribosomal proteins generates protein-specific cell cycle and morphological phenotypes

Molecular Biology of the Cell ◽

10.1091/mbc.e13-02-0097 ◽

2013 ◽

Vol 24 (23) ◽

pp. 3620-3633 ◽

Cited By ~ 18

Author(s):

Mamata Thapa ◽

Ananth Bommakanti ◽

Md. Shamsuzzaman ◽

Brian Gregory ◽

Leigh Samsel ◽

...

Keyword(s):

Cell Cycle ◽

Cell Fate ◽

Ribosomal Proteins ◽

Ribosome Biogenesis ◽

Cell Cycle Progression ◽

Physical Structure ◽

Specific Cell ◽

M Cell ◽

Cycle Progression ◽

M Phase

The biogenesis of ribosomes is coordinated with cell growth and proliferation. Distortion of the coordinated synthesis of ribosomal components affects not only ribosome formation, but also cell fate. However, the connection between ribosome biogenesis and cell fate is not well understood. To establish a model system for inquiries into these processes, we systematically analyzed cell cycle progression, cell morphology, and bud site selection after repression of 54 individual ribosomal protein (r-protein) genes in Saccharomyces cerevisiae. We found that repression of nine 60S r-protein genes results in arrest in the G2/M phase, whereas repression of nine other 60S and 22 40S r-protein genes causes arrest in the G1 phase. Furthermore, bud morphology changes after repression of some r-protein genes. For example, very elongated buds form after repression of seven 60S r-protein genes. These genes overlap with, but are not identical to, those causing the G2/M cell cycle phenotype. Finally, repression of most r-protein genes results in changed sites of bud formation. Strikingly, the r-proteins whose repression generates similar effects on cell cycle progression cluster in the ribosome physical structure, suggesting that different topological areas of the precursor and/or mature ribosome are mechanistically connected to separate aspects of the cell cycle.

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