scholarly journals XMU-MP-1 induces growth arrest in a model human mini-organ and antagonises cell cycle-dependent paclitaxel cytotoxicity

Cell Division ◽  
2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Ellen Mitchell ◽  
Charlotte E. L. Mellor ◽  
Talveen S. Purba
Keyword(s):  
Cell Cycle ◽  
Hair Follicle ◽  
Cell Cycle Progression ◽  
Hippo Pathway ◽  
Ki 67 ◽  
Hair Matrix ◽  
Novel Strategy ◽  
Target Effect ◽  
Cycle Dependent ◽  
The Hippo Pathway

Abstract Background XMU-MP-1 is an inhibitor of the Hippo pathway kinases MST1/2 and has been shown to promote the downstream activation of the pro-proliferative, pro-regenerative and anti-apoptotic transcriptional regulator YAP1. We tested whether XMU-MP-1 can activate YAP1 in a model human mini-organ, namely the hair follicle, to determine whether it can be pharmacologically exploited to promote regeneration in the hair follicle as a novel strategy to treat pathological hair loss disorders. Results XMU-MP-1 treatment inhibited MOB1 phosphorylation but did not increase active YAP1 in the hair follicle. Rather than promote proliferation, XMU-MP-1 serendipitously decreased the number of Ki-67+, EdU+ and phospho histone H3+ hair matrix keratinocytes and antagonised the cytotoxic effects of paclitaxel. Conclusions XMU-MP-1 perturbs epithelial cell cycle progression in a model human mini-organ. This may arise as an off-target effect, especially when XMU-MP-1 has been described to strongly inhibit 21 additional kinases beyond MST1/2. Therefore, whilst these effects may be dependent on tissue context, researchers should exercise caution when interpreting the effects of XMU-MP-1, especially in tissues with actively proliferating cell populations.

Phospho-regulation of KIBRA by CDK1 and CDC14 phosphatase controls cell-cycle progression

2012 ◽  
Vol 447 (1) ◽  
pp. 93-102 ◽  
Author(s):  
Ming Ji ◽  
Shuping Yang ◽  
Yuanhong Chen ◽  
Ling Xiao ◽  
Lin Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Memory Performance ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Cycle Progression ◽  
Mitotic Kinases ◽  
The Hippo Pathway

KIBRA (kidney- and brain-expressed protein) is a novel regulator of the Hippo pathway, which controls tissue growth and tumorigenesis by regulating both cell proliferation and apoptosis. In mammals, KIBRA is associated with memory performance. The physiological function and regulation of KIBRA in non-neuronal cells remain largely unclear. We reported recently that KIBRA is phosphorylated by the mitotic kinases Aurora-A and -B. In the present study, we have expanded our analysis of KIBRA's role in cell-cycle progression. We show that KIBRA is also phosphorylated by CDK1 (cyclin-dependent kinase 1) in response to spindle damage stress. We have identified KIBRA Ser542 and Ser931 as main phosphorylation sites for CDK1 both in vitro and in vivo. Moreover, we found that the CDC (cell division cycle) 14A/B phosphatases associate with KIBRA, and CDK1-non-phosphorylatable KIBRA has greatly reduced interaction with CDC14B. CDC14A/B dephosphorylate CDK1-phosphorylated KIBRA in vitro and in cells. By using inducible-expression cell lines, we show further that phospho-regulation of KIBRA by CDK1 and CDC14 is involved in mitotic exit under spindle stress. Our results reveal a new mechanism through which KIBRA regulates cell-cycle progression.

scholarly journals The Hippo Signaling Pathway in Cancer: A Cell Cycle Perspective

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6214
Author(s):  
Yi Xiao ◽  
Jixin Dong
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Functional Conservation ◽  
The Core ◽  
The Hippo Pathway ◽  
Cycle Regulation

Cell cycle progression is an elaborate process that requires stringent control for normal cellular function. Defects in cell cycle control, however, contribute to genomic instability and have become a characteristic phenomenon in cancers. Over the years, advancement in the understanding of disrupted cell cycle regulation in tumors has led to the development of powerful anti-cancer drugs. Therefore, an in-depth exploration of cell cycle dysregulation in cancers could provide therapeutic avenues for cancer treatment. The Hippo pathway is an evolutionarily conserved regulator network that controls organ size, and its dysregulation is implicated in various types of cancers. Although the role of the Hippo pathway in oncogenesis has been widely investigated, its role in cell cycle regulation has not been comprehensively scrutinized. Here, we specifically focus on delineating the involvement of the Hippo pathway in cell cycle regulation. To that end, we first compare the structural as well as functional conservation of the core Hippo pathway in yeasts, flies, and mammals. Then, we detail the multi-faceted aspects in which the core components of the mammalian Hippo pathway and their regulators affect the cell cycle, particularly with regard to the regulation of E2F activity, the G1 tetraploidy checkpoint, DNA synthesis, DNA damage checkpoint, centrosome dynamics, and mitosis. Finally, we briefly discuss how a collective understanding of cell cycle regulation and the Hippo pathway could be weaponized in combating cancer.

Cell cycle-dependent reactivity with the monoclonal antibody Ki-67 during myeloid cell differentiation

1988 ◽  
Vol 179 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Robert P. Wersto ◽  
Fritz Herz ◽  
Robert E. Gallagher ◽  
Leopold G. Koss
Keyword(s):  
Cell Cycle ◽  
Monoclonal Antibody ◽  
Cell Differentiation ◽  
Myeloid Cell ◽  
Ki 67 ◽  
Cycle Dependent

Exogenous ATP induces a limited cell cycle progression of arterial smooth muscle cells

1993 ◽  
Vol 264 (4) ◽  
pp. C783-C788 ◽  
Author(s):  
R. Malam-Souley ◽  
M. Campan ◽  
A. P. Gadeau ◽  
C. Desgranges
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cell Cycle Progression ◽  
Mrna Level ◽  
Muscle Cells ◽  
Arterial Smooth Muscle ◽  
Cycle Progression ◽  
Arterial Smooth Muscle Cells ◽  
Cycle Dependent

Because exogenous ATP is suspected to influence the proliferative process, its effects on the cell cycle progression of arterial smooth muscle cells were studied by investigating changes in the mRNA steady-state level of cell cycle-dependent genes. Stimulation of cultured quiescent smooth muscle cells by exogenous ATP induced chronological activation not only of immediate-early but also of delayed-early cell cycle-dependent genes, which were usually expressed after a mitogenic stimulation. In contrast, ATP did not increase late G1 gene mRNA level, demonstrating that this nucleotide induces a limited cell cycle progression of arterial smooth muscle cells through the G1 phase but is not able by itself to induce crossing over the G1-S boundary and consequently DNA synthesis. An increase in c-fos mRNA level was also induced by ADP but not by AMP or adenosine. Moreover, 2-methylthioadenosine 5'-triphosphate but not alpha, beta-methyleneadenosine 5'-triphosphate mediated this kind of response. Taken together, these results demonstrate that extracellular ATP induces the limited progression of arterial smooth muscle cells through the G1 phase via its fixation on P2 gamma receptors.

The murine Ki-67 cell proliferation antigen accumulates in the nucleolar and heterochromatic regions of interphase cells and at the periphery of the mitotic chromosomes in a process essential for cell cycle progression

1996 ◽  
Vol 109 (1) ◽  
pp. 143-153 ◽  
Author(s):  
M. Starborg ◽  
K. Gell ◽  
E. Brundell ◽  
C. Hoog
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Tandem Repeats ◽  
Sequence Motifs ◽  
Mitotic Chromosomes ◽  
Proliferating Cells ◽  
Ki 67 ◽  
Cycle Progression ◽  
Conserved Sequence ◽  
Interphase Cells

We have isolated the murine homologue of the human Ki-67 antigen. The Ki-67 antigen is used as a marker to assess the proliferative capacity of tumour cells; however, its cellular function is not known. The murine Ki-67 cDNA sequence (TSG126) was found to contain 13 tandem repeats, making up more than half of the total protein size. A comparison of this repetitive sequence block to its human counterpart, which contains 16 consecutive repeat units, revealed several conserved sequence motifs, including one motif frequently observed in proteins interacting with DNA. An antiserum developed against the product of the TSG126 cDNA clone identified a protein with an apparent molecular mass of 360 kDa, mainly expressed in proliferating cells. The TSG126 protein begins to accumulate during the late G1 stage of the cell cycle and is first seen as numerous small granules evenly distributed throughout the nucleus. During the S and the G2 phases, larger foci that overlap with the nucleoli and the heterochromatic regions are formed. At the onset of mitosis the TSG126 protein undergoes a dramatic redistribution process and becomes associated with the surface of the condensed chromosomes. The relative absence of the TSG126 protein from G1 interphase cells strongly argues against a model where the association of the TSG126 protein with mitotic chromosomes merely reflects a mechanism for the symmetrical distribution of nucleolar proteins between daughter cells. Instead, the intracellular distribution of the TSG126 protein during the cell cycle suggests that it could have a chromatin-associated function in both interphase and mitotic cells. Microinjection of anti-TSG126 antibodies into proliferating Swiss-3T3 fibroblasts was found to delay cell cycle progression, indicating that the TSG126 protein has an essential nuclear function.

Abstract 396: Regulation of Cardiomyocyte Proliferation by the Hippo Pathway and Dystrophin Complex

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Yuka Morikawa ◽  
John Leach ◽  
Todd Heallen ◽  
Ge Tao ◽  
James F Martin
Keyword(s):  
Cell Cycle ◽  
Muscular Dystrophy ◽  
Dna Synthesis ◽  
De Novo ◽  
Hippo Pathway ◽  
Myocardial Damage ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Heart Repair ◽  
The Hippo Pathway

Regeneration in mammalian hearts is limited due to the extremely low renewal rate of cardiomyocytes and their inability to reenter the cell cycle. In rodent hearts, endogenous regenerative capacity exists during development but is rapidly repressed after birth, at which time growth is by hypertrophy. During the developmental and neonatal periods, heart regeneration occurs through proliferation of pre-existing cardiomyocytes. Our approach of activating heart regeneration is to uncover the mechanisms responsible for repression of cardiomyocyte proliferation. The Hippo pathway controls heart size by repressing cardiomyocyte proliferation during development. By deleting Salv , a modulator of the Hippo pathway, we found that myocardial damage in postnatal and adult hearts was repaired both anatomically and functionally. This heart repair occurred primary through proliferation of preexisting cardiomyocytes. During repair, cardiomyocytes reenter the cell cycle; de novo DNA synthesis, karyokinesis, and cytokinesis all take place. The dystrophin glycoprotein complex (DGC) is essential for muscle maintenance by anchoring the cytoskeleton and extracellular matrix. Disruption of the DGC results in muscular dystrophies, including Duchenne muscular dystrophy, resulting in both skeletal and cardiac myopathies. Recently the DGC was shown to regulate cardiomyocyte proliferation and we found that the DGC and the Hippo pathway components directly interact. To address if the DGC and the Hippo pathway coordinately regulate cardiomyocyte proliferation, we conditionally deleted Salv in the mouse model of muscular dystrophy, the mdx line. We found that simultaneous disruption of both the DGC and Hippo pathway leads an increased de novo DNA synthesis and cytokinesis in cardiomyocytes after heart damage. Our findings provide new insights into the mechanisms leading to heart repair through proliferation of endogenous cardiomyocytes.

scholarly journals CDK4/6 inhibitors: a novel strategy for tumor radiosensitization

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Yilan Yang ◽  
Jurui Luo ◽  
Xingxing Chen ◽  
Zhaozhi Yang ◽  
Xin Mei ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Clinical Studies ◽  
Cell Cycle Progression ◽  
Combined Therapy ◽  
Small Sample ◽  
Combination Strategies ◽  
Novel Strategy ◽  
Underlying Mechanisms

Abstract Recently, the focus of enhancing tumor radiosensitivity has shifted from chemotherapeutics to targeted therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a novel class of selective cell cycle therapeutics that target the cyclin D-CDK4/6 complex and induce G1 phase arrest. These agents have demonstrated favorable effects when used as monotherapy or combined with endocrine therapy and targeted inhibitors, stimulating further explorations of other combination strategies. Multiple preclinical studies have indicated that CDK4/6 inhibitors exhibit a synergistic effect with radiotherapy both in vitro and in vivo. The principal mechanisms of radiosensitization effects include inhibition of DNA damage repair, enhancement of apoptosis, and blockade of cell cycle progression, which provide the rationale for clinical use. CDK4/6 inhibitors also induce cellular senescence and promote anti-tumor immunity, which might represent potential mechanisms for radiosensitization. Several small sample clinical studies have preliminarily indicated that the combination of CDK4/6 inhibitors and radiotherapy exhibited well-tolerated toxicity and promising efficacy. However, most clinical trials in combined therapy remain in the recruitment stage. Further work is required to seek optimal radiotherapy-drug combinations. In this review, we describe the effects and underlying mechanisms of CDK4/6 inhibitors as a radiosensitizer and discuss previous clinical studies to evaluate the prospects and challenges of this combination.

scholarly journals Time varying mobility and turnover of actomyosin ring components during cytokinesis in Schizosaccharomyces pombe

2020 ◽  
pp. mbc.E20-09-0588
Author(s):  
Anton Kamnev ◽  
Saravanan Palani ◽  
Paola Zambon ◽  
Tom Cheffings ◽  
Nigel Burroughs ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Schizosaccharomyces Pombe ◽  
Fluorescence Recovery After Photobleaching ◽  
Myosin Ii ◽  
Cellular Structures ◽  
Time Varying ◽  
Mobile Fraction ◽  
Novel Strategy ◽  
Cycle Dependent ◽  
Mobile Protein

Cytokinesis in many eukaryotes is dependent on a contractile actomyosin ring (AMR), composed of F-actin, myosin II, and other actin and myosin II regulators. Through fluorescence recovery after photobleaching experiments, many components of the AMR have been shown to be mobile and to undergo constant exchange with the cytosolic pools. However, how the mobility of its components changes at distinct stages of mitosis and cytokinesis has not been addressed. Here, we describe the mobility of eight Schizosaccharomyces pombe AMR proteins at different stages of mitosis and cytokinesis using an approach we have developed. We identified 3 classes of proteins, which showed 1) high (Ain1, Myo2, Myo51), 2) low (Rng2, Mid1, Myp2, Cdc12), and 3) cell cycle dependent (Cdc15) mobile fractions. We observed that the F-BAR protein Cdc15 undergoes a 20∼30% reduction in its mobile fraction after spindle breakdown and initiation of AMR contraction. Moreover, our data indicate that this change in Cdc15 mobility is dependent on the SIN-signalling pathway. Our work offers a novel strategy to estimate cell cycle-dependent mobile protein fractions in cellular structures and provides a valuable dataset, that is of interest to researchers working on cytokinesis.

scholarly journals The NDR Kinase DBF-2 Is Involved in Regulation of Mitosis, Conidial Development, and Glycogen Metabolism in Neurospora crassa

2009 ◽  
Vol 9 (4) ◽  
pp. 502-513 ◽  
Author(s):  
Efrat Dvash ◽  
Galia Kra-Oz ◽  
Carmit Ziv ◽  
Shmuel Carmeli ◽  
Oded Yarden
Keyword(s):  
Cell Cycle ◽  
Neurospora Crassa ◽  
Filamentous Fungus ◽  
Hippo Pathway ◽  
Glycogen Metabolism ◽  
Content Type ◽  
Protein Levels ◽  
Carbon Nitrogen Ratio ◽  
Cdc 2 ◽  
The Hippo Pathway

ABSTRACT Neurospora crassa dbf-2 encodes an NDR (nuclear Dbf2-related) protein kinase, homologous to LATS1, a core component of the Hippo pathway. This pathway plays important roles in restraining cell proliferation and promoting apoptosis in differentiating cells. Here, we demonstrate that DBF-2 is involved in three fundamental processes in a filamentous fungus: cell cycle regulation, glycogen biosynthesis, and conidiation. DBF-2 is predominantly localized to the nucleus, and most (approximately 60%) dbf-2 null mutant nuclei are delayed in mitosis, indicating that DBF-2 activity is required for properly completing the cell cycle. The dbf-2 mutant exhibits reduced basal hyphal extension rates accompanied by a carbon/nitrogen ratio-dependent bursting of hyphal tips, vast glycogen leakage, defects in aerial hypha formation, and impairment of all three asexual conidiation pathways in N. crassa. Our findings also indicate that DBF-2 is essential for sexual reproduction in a filamentous fungus. Defects in other Hippo and glycogen metabolism pathway components (mob-1, ccr-4, mst-1, and gsk-3) share similar phenotypes such as mitotic delay and decreased CDC-2 (cell division cycle 2) protein levels, massive hyphal swellings, hyphal tip bursting, glycogen leakage, and impaired conidiation. We propose that DBF-2 functions as a link between Hippo and glycogen metabolism pathways.

scholarly journals Structural mechanism of Myb–MuvB assembly

2018 ◽  
Vol 115 (40) ◽  
pp. 10016-10021 ◽  
Author(s):  
Keelan Z. Guiley ◽  
Audra N. Iness ◽  
Siddharth Saini ◽  
Sarvind Tripathi ◽  
Joseph S. Lipsick ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Biochemical Analysis ◽  
Adaptor Protein ◽  
Cancer Cell Proliferation ◽  
Cycle Progression ◽  
Structural Mechanism ◽  
Transcriptional Regulatory ◽  
Regulatory Complex ◽  
Cycle Dependent

The MuvB transcriptional regulatory complex, which controls cell-cycle-dependent gene expression, cooperates with B-Myb to activate genes required for the G2 and M phases of the cell cycle. We have identified the domain in B-Myb that is essential for the assembly of the Myb–MuvB (MMB) complex. We determined a crystal structure that reveals how this B-Myb domain binds MuvB through the adaptor protein LIN52 and the scaffold protein LIN9. The structure and biochemical analysis provide an understanding of how oncogenic B-Myb is recruited to regulate genes required for cell-cycle progression, and the MMB interface presents a potential therapeutic target to inhibit cancer cell proliferation.

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