Cell cycle control in cancer Matthews, Helen K; Bertoli, Cosetta; de Bruin, Robertus A M
Nature reviews. Molecular cell biology,
01/2022, Letnik:
23, Številka:
1
Journal Article
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Cancer is a group of diseases in which cells divide continuously and excessively. Cell division is tightly regulated by multiple evolutionarily conserved cell cycle control mechanisms, to ensure the ...production of two genetically identical cells. Cell cycle checkpoints operate as DNA surveillance mechanisms that prevent the accumulation and propagation of genetic errors during cell division. Checkpoints can delay cell cycle progression or, in response to irreparable DNA damage, induce cell cycle exit or cell death. Cancer-associated mutations that perturb cell cycle control allow continuous cell division chiefly by compromising the ability of cells to exit the cell cycle. Continuous rounds of division, however, create increased reliance on other cell cycle control mechanisms to prevent catastrophic levels of damage and maintain cell viability. New detailed insights into cell cycle control mechanisms and their role in cancer reveal how these dependencies can be best exploited in cancer treatment.
Background Identifying genetic syndromes that lead to significant atopic disease can open new pathways for investigation and intervention in allergy. Objective We sought to define a genetic syndrome ...of severe atopy, increased serum IgE levels, immune deficiency, autoimmunity, and motor and neurocognitive impairment. Methods Eight patients from 2 families with similar syndromic features were studied. Thorough clinical evaluations, including brain magnetic resonance imaging and sensory evoked potentials, were performed. Peripheral lymphocyte flow cytometry, antibody responses, and T-cell cytokine production were measured. Whole-exome sequencing was performed to identify disease-causing mutations. Immunoblotting, quantitative RT-PCR, enzymatic assays, nucleotide sugar, and sugar phosphate analyses, along with matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry of glycans, were used to determine the molecular consequences of the mutations. Results Marked atopy and autoimmunity were associated with increased TH 2 and TH 17 cytokine production by CD4+ T cells. Bacterial and viral infection susceptibility were noted along with T-cell lymphopenia, particularly of CD8+ T cells, and reduced memory B-cell numbers. Apparent brain hypomyelination resulted in markedly delayed evoked potentials and likely contributed to neurologic abnormalities. Disease segregated with novel autosomal recessive mutations in a single gene, phosphoglucomutase 3 ( PGM3 ). Although PGM3 protein expression was variably diminished, impaired function was demonstrated by decreased enzyme activity and reduced uridine diphosphate–N-acetyl-D-glucosamine, along with decreased O- and N-linked protein glycosylation in patients' cells. These results define a new congenital disorder of glycosylation. Conclusions Autosomal recessive hypomorphic PGM3 mutations underlie a disorder of severe atopy, immune deficiency, autoimmunity, intellectual disability, and hypomyelination.
As they enter mitosis, animal cells undergo profound actin-dependent changes in shape to become round. Here we identify the Cdk1 substrate, Ect2, as a central regulator of mitotic rounding, thus ...uncovering a link between the cell-cycle machinery that drives mitotic entry and its accompanying actin remodeling. Ect2 is a RhoGEF that plays a well-established role in formation of the actomyosin contractile ring at mitotic exit, through the local activation of RhoA. We find that Ect2 first becomes active in prophase, when it is exported from the nucleus into the cytoplasm, activating RhoA to induce the formation of a mechanically stiff and rounded metaphase cortex. Then, at anaphase, binding to RacGAP1 at the spindle midzone repositions Ect2 to induce local actomyosin ring formation. Ect2 localization therefore defines the stage-specific changes in actin cortex organization critical for accurate cell division.
► Ect2 drives dynamic changes in cell shape throughout mitosis ► Ect2 induces actin-dependent changes in cortical mechanics at mitotic onset ► Ect2's distinct functions are achieved through changes in subcellular localization ► Actin remodeling for animal cell division begins at mitotic entry
Cell division is accompanied by dramatic changes in cell shape, which Matthews et al. show are regulated by the Cdk1 substrate Ect2. At mitotic onset, Ect2 leaves the nucleus to activate RhoA and cortical actomyosin, driving mitotic rounding. It is then repositioned at mitotic exit to drive actomyosin ring formation.
Mutations in RAS are key oncogenic drivers and therapeutic targets. Oncogenic Ras proteins activate a network of downstream signalling pathways, including extracellular signal-regulated kinase (ERK) ...and phosphatidylinositol 3-kinase (PI3K), promoting cell proliferation and survival. However, there is increasing evidence that RAS oncogenes also alter the mechanical properties of both individual malignant cells and transformed tissues. Here we discuss the role of oncogenic RAS in controlling mechanical cell phenotypes and how these mechanical changes promote oncogenic transformation in single cells and tissues. RAS activation alters actin organisation and actomyosin contractility. These changes alter cell rheology and impact mechanosensing through changes in substrate adhesion and YAP/TAZ-dependent mechanotransduction. We then discuss how these changes play out in cell collectives and epithelial tissues by driving large-scale tissue deformations and the expansion of malignant cells. Uncovering how RAS oncogenes alter cell mechanics will lead to a better understanding of the morphogenetic processes that underlie tumour formation in RAS-mutant cancers.
The role of altered tissue mechanics in early cancer development is not well understood. A new study reveals how oncogene activation generates force within a tissue to impact cell division in ...surrounding normal cells, which then contribute to tumour formation.
The role of altered tissue mechanics in early cancer development is not well understood. A new study reveals how oncogene activation generates force within a tissue to impact cell division in surrounding normal cells, which then contribute to tumour formation.
The Mechanics of Mitotic Cell Rounding Taubenberger, Anna V; Baum, Buzz; Matthews, Helen K
Frontiers in cell and developmental biology,
08/2020, Letnik:
8
Journal Article
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When animal cells enter mitosis, they round up to become spherical. This shape change is accompanied by changes in mechanical properties. Multiple studies using different measurement methods have ...revealed that cell surface tension, intracellular pressure and cortical stiffness increase upon entry into mitosis. These cell-scale, biophysical changes are driven by alterations in the composition and architecture of the contractile acto-myosin cortex together with osmotic swelling and enable a mitotic cell to exert force against the environment. When the ability of cells to round is limited, for example by physical confinement, cells suffer severe defects in spindle assembly and cell division. The requirement to push against the environment to create space for spindle formation is especially important for cells dividing in tissues. Here we summarize the evidence and the tools used to show that cells exert rounding forces in mitosis
and
, review the molecular basis for this force generation and discuss its function for ensuring successful cell division in single cells and for cells dividing in normal or diseased tissues.
Animal cells undergo a dramatic series of shape changes as they divide, which depend on re-modeling of cell-substrate adhesions. Here, we show that while focal adhesion complexes are disassembled ...during mitotic rounding, integrins remain in place. These integrin-rich contacts connect mitotic cells to the underlying substrate throughout mitosis, guide polarized cell migration following mitotic exit, and are functionally important, since adherent cells undergo division failure when removed from the substrate. Further, the ability of cells to re-spread along pre-existing adhesive contacts is essential for division in cells compromised in their ability to construct a RhoGEF-dependent (Ect2) actomyosin ring. As a result, following Ect2 depletion, cells fail to divide on small adhesive islands but successfully divide on larger patterns, as the connection between daughter cells narrows and severs as they migrate away from one another. In this way, regulated re-modeling of cell-substrate adhesions during mitotic rounding aids division in animal cells.
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•Cells re-model adhesions as they round up upon entry into mitosis•These cell-substrate adhesions are essential for division in non-transformed cells•Adhesions can guide migration to divide cells with a compromised actomyosin ring
Dix et al. show that the integrin-positive adhesive contacts that remain following mitotic rounding are essential for division in non-transformed adherent cells in culture. Further, these adhesion sites guide polarized daughter cell migration—a process that is sufficient to drive abscission in the absence of a visible contractile actomyosin ring.
Mutations in the LRBA gene (encoding the lipopolysaccharide-responsive and beige-like anchor protein) cause a syndrome of autoimmunity, lymphoproliferation, and humoral immune deficiency. The ...biological role of LRBA in immunologic disease is unknown. We found that patients with LRBA deficiency manifested a dramatic and sustained improvement in response to abatacept, a CTLA4 (cytotoxic T lymphocyte antigen-4)–immunoglobulin fusion drug. Clinical responses and homology of LRBA to proteins controlling intracellular trafficking led us to hypothesize that it regulates CTLA4, a potent inhibitory immune receptor. We found that LRBA colocalized with CTLA4 in endosomal vesicles and that LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in reduced levels of CTLA4 protein in FoxP3+ regulatory and activated conventional T cells. In LRBA-deficient cells, inhibition of lysosome degradation with chloroquine prevented CTLA4 loss. These findings elucidate a mechanism for CTLA4 trafficking and control of immune responses and suggest therapies for diseases involving the CTLA4 pathway.
To divide in a tissue, both normal and cancer cells become spherical and mechanically stiffen as they enter mitosis. We investigated the effect of oncogene activation on this process in normal ...epithelial cells. We found that short-term induction of oncogenic RasV12 activates downstream mitogen-activated protein kinase (MEK-ERK) signaling to alter cell mechanics and enhance mitotic rounding, so that RasV12-expressing cells are softer in interphase but stiffen more upon entry into mitosis. These RasV12-dependent changes allow cells to round up and divide faithfully when confined underneath a stiff hydrogel, conditions in which normal cells and cells with reduced levels of Ras-ERK signaling suffer multiple spindle assembly and chromosome segregation errors. Thus, by promoting cell rounding and stiffening in mitosis, oncogenic RasV12 enables cells to proliferate under conditions of mechanical confinement like those experienced by cells in crowded tumors.
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•Ras-ERK signaling controls cell shape in mitosis•Activation of Ras alters cell mechanics to enhance mitotic stiffening•Cells expressing Ras are better able to round up to divide under stiff gels•Ras limits DNA segregation errors normally observed in confined cell division
Matthews et al. show that activation of the oncogenic Ras-ERK signaling pathway changes the shape and mechanical properties of normal epithelial cells in mitosis. This enables Ras-activated cells to round up and accurately segregate chromosomes when dividing in conditions of mechanical confinement.
Contact inhibition of locomotion was discovered by Abercrombie more than 50 years ago and describes the behaviour of fibroblast cells confronting each other in vitro, where they retract their ...protrusions and change direction on contact. Its failure was suggested to contribute to malignant invasion. However, the molecular basis of contact inhibition of locomotion and whether it also occurs in vivo are still unknown. Here we show that neural crest cells, a highly migratory and multipotent embryonic cell population, whose behaviour has been likened to malignant invasion, demonstrate contact inhibition of locomotion both in vivo and in vitro, and that this accounts for their directional migration. When two migrating neural crest cells meet, they stop, collapse their protrusions and change direction. In contrast, when a neural crest cell meets another cell type, it fails to display contact inhibition of locomotion; instead, it invades the other tissue, in the same manner as metastatic cancer cells. We show that inhibition of non-canonical Wnt signalling abolishes both contact inhibition of locomotion and the directionality of neural crest migration. Wnt-signalling members localize at the site of cell contact, leading to activation of RhoA in this region. These results provide the first example of contact inhibition of locomotion in vivo, provide an explanation for coherent directional migration of groups of cells and establish a previously unknown role for non-canonical Wnt signalling.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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