scholarly journals The Phosphorylation Status of Drp1-Ser637 by PKA in Mitochondrial Fission Modulates Mitophagy via PINK1/Parkin to Exert Multipolar Spindles Assembly during Mitosis

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 424
Author(s):  
Huey-Jiun Ko ◽  
Cheng-Yu Tsai ◽  
Shean-Jaw Chiou ◽  
Yun-Ling Lai ◽  
Chi-Huei Wang ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Mitochondrial Fission ◽  
Complex Iii ◽  
Cyclin B ◽  
Aurora A ◽  
Cycle Progression ◽  
Mitotic Kinases ◽  
Multipolar Spindles ◽  
M Phase ◽  
Associated Proteins

Mitochondrial fission and fusion cycles are integrated with cell cycle progression. Here we first re-visited how mitochondrial ETC inhibition disturbed mitosis progression, resulting in multipolar spindles formation in HeLa cells. Inhibitors of ETC complex I (rotenone, ROT) and complex III (antimycin A, AA) decreased the phosphorylation of Plk1 T210 and Aurora A T288 in the mitotic phase (M-phase), especially ROT, affecting the dynamic phosphorylation status of fission protein dynamin-related protein 1 (Drp1) and the Ser637/Ser616 ratio. We then tested whether specific Drp1 inhibitors, Mdivi-1 or Dynasore, affected the dynamic phosphorylation status of Drp1. Similar to the effects of ROT and AA, our results showed that Mdivi-1 but not Dynasore influenced the dynamic phosphorylation status of Ser637 and Ser616 in Drp1, which converged with mitotic kinases (Cdk1, Plk1, Aurora A) and centrosome-associated proteins to significantly accelerate mitotic defects. Moreover, our data also indicated that evoking mito-Drp1-Ser637 by protein kinase A (PKA) rather than Drp1-Ser616 by Cdk1/Cyclin B resulted in mitochondrial fission via the PINK1/Parkin pathway to promote more efficient mitophagy and simultaneously caused multipolar spindles. Collectively, this study is the first to uncover that mito-Drp1-Ser637 by PKA, but not Drp1-Ser616, drives mitophagy to exert multipolar spindles formation during M-phase.

scholarly journals Canonical and Alternative Pathways in Cyclin-Dependent Kinase 1/Cyclin B Inactivation upon M-Phase Exit in Xenopus laevis Cell-Free Extracts

2011 ◽  
Vol 2011 ◽  
pp. 1-8
Author(s):  
Jacek Z. Kubiak ◽  
Mohammed El Dika
Keyword(s):  
Cell Cycle ◽  
Xenopus Laevis ◽  
Cell Cycle Progression ◽  
Cyclin B ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Alternative Pathways ◽  
Global View ◽  
M Phase

Cyclin-Dependent Kinase 1 (CDK1) is the major M-phase kinase known also as the M-phase Promoting Factor or MPF. Studies performed during the last decade have shown many details of how CDK1 is regulated and also how it regulates the cell cycle progression. Xenopus laevis cell-free extracts were widely used to elucidate the details and to obtain a global view of the role of CDK1 in M-phase control. CDK1 inactivation upon M-phase exit is a primordial process leading to the M-phase/interphase transition during the cell cycle. Here we discuss two closely related aspects of CDK1 regulation in Xenopus laevis cell-free extracts: firstly, how CDK1 becomes inactivated and secondly, how other actors, like kinases and phosphatases network and/or specific inhibitors, cooperate with CDK1 inactivation to assure timely exit from the M-phase.

scholarly journals Targeting RB1 Loss in Cancers

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3737
Author(s):  
Paing Linn ◽  
Susumu Kohno ◽  
Jindan Sheng ◽  
Nilakshi Kulathunga ◽  
Hai Yu ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Suppressor Gene ◽  
Therapeutic Approaches ◽  
Neighboring Gene ◽  
Genomic Aberration ◽  
Cycle Progression ◽  
Synthetic Lethal ◽  
Mitotic Kinases ◽  
Promote Cell Cycle Progression ◽  
Almost All

Retinoblastoma protein 1 (RB1) is encoded by a tumor suppressor gene that was discovered more than 30 years ago. Almost all mitogenic signals promote cell cycle progression by braking on the function of RB1 protein through mono- and subsequent hyper-phosphorylation mediated by cyclin-CDK complexes. The loss of RB1 function drives tumorigenesis in limited types of malignancies including retinoblastoma and small cell lung cancer. In a majority of human cancers, RB1 function is suppressed during tumor progression through various mechanisms. The latter gives rise to the acquisition of various phenotypes that confer malignant progression. The RB1-targeted molecules involved in such phenotypic changes are good quarries for cancer therapy. Indeed, a variety of novel therapies have been proposed to target RB1 loss. In particular, the inhibition of a number of mitotic kinases appeared to be synthetic lethal with RB1 deficiency. A recent study focusing on a neighboring gene that is often collaterally deleted together with RB1 revealed a pharmacologically targetable vulnerability in RB1-deficient cancers. Here we summarize current understanding on possible therapeutic approaches targeting functional or genomic aberration of RB1 in cancers.

scholarly journals Cdk1-Mediated Phosphorylation of Human ATF7 at Thr-51 and Thr-53 Promotes Cell-Cycle Progression into M Phase

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e116048 ◽  
Author(s):  
Hitomi Hasegawa ◽  
Kenichi Ishibashi ◽  
Shoichi Kubota ◽  
Chihiro Yamaguchi ◽  
Ryuzaburo Yuki ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
M Phase

scholarly journals Loss of MCU prevents mitochondrial fusion in G1-S phase and blocks cell cycle progression and proliferation

2019 ◽  
Vol 12 (579) ◽  
pp. eaav1439 ◽  
Author(s):  
Olha M. Koval ◽  
Emily K. Nguyen ◽  
Velarchana Santhana ◽  
Trevor P. Fidler ◽  
Sara C. Sebag ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Cycle Phase ◽  
Wild Type ◽  
Mitochondrial Fragmentation ◽  
Cycle Progression ◽  
Regulatory Circuit

The role of the mitochondrial Ca2+uniporter (MCU) in physiologic cell proliferation remains to be defined. Here, we demonstrated that the MCU was required to match mitochondrial function to metabolic demands during the cell cycle. During the G1-S transition (the cycle phase with the highest mitochondrial ATP output), mitochondrial fusion, oxygen consumption, and Ca2+uptake increased in wild-type cells but not in cells lacking MCU. In proliferating wild-type control cells, the addition of the growth factors promoted the activation of the Ca2+/calmodulin-dependent kinase II (CaMKII) and the phosphorylation of the mitochondrial fission factor Drp1 at Ser616. The lack of the MCU was associated with baseline activation of CaMKII, mitochondrial fragmentation due to increased Drp1 phosphorylation, and impaired mitochondrial respiration and glycolysis. The mitochondrial fission/fusion ratio and proliferation in MCU-deficient cells recovered after MCU restoration or inhibition of mitochondrial fragmentation or of CaMKII in the cytosol. Our data highlight a key function for the MCU in mitochondrial adaptation to the metabolic demands during cell cycle progression. Cytosolic CaMKII and the MCU participate in a regulatory circuit, whereby mitochondrial Ca2+uptake affects cell proliferation through Drp1.

scholarly journals Regulation of Cell Cycle Progression by Growth Factor-Induced Cell Signaling

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3327
Author(s):  
Zhixiang Wang
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Tyrosine Kinases ◽  
Cell Cycle Progression ◽  
Phase Cell ◽  
Growth Factor Signaling ◽  
Cycle Progression ◽  
M Phase

The cell cycle is the series of events that take place in a cell, which drives it to divide and produce two new daughter cells. The typical cell cycle in eukaryotes is composed of the following phases: G1, S, G2, and M phase. Cell cycle progression is mediated by cyclin-dependent kinases (Cdks) and their regulatory cyclin subunits. However, the driving force of cell cycle progression is growth factor-initiated signaling pathways that control the activity of various Cdk–cyclin complexes. While the mechanism underlying the role of growth factor signaling in G1 phase of cell cycle progression has been largely revealed due to early extensive research, little is known regarding the function and mechanism of growth factor signaling in regulating other phases of the cell cycle, including S, G2, and M phase. In this review, we briefly discuss the process of cell cycle progression through various phases, and we focus on the role of signaling pathways activated by growth factors and their receptor (mostly receptor tyrosine kinases) in regulating cell cycle progression through various phases.

scholarly journals Akt/Protein Kinase B-Dependent Phosphorylation and Inactivation of WEE1Hu Promote Cell Cycle Progression at G2/M Transition

2005 ◽  
Vol 25 (13) ◽  
pp. 5725-5737 ◽  
Author(s):  
Kazuhiro Katayama ◽  
Naoya Fujita ◽  
Takashi Tsuruo
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Phosphorylation Site ◽  
Cytoplasmic Localization ◽  
M Cell ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
M Phase ◽  
Promote Cell Cycle Progression

ABSTRACT The serine/threonine kinase Akt is known to promote cell growth by regulating the cell cycle in G1 phase through activation of cyclin/Cdk kinases and inactivation of Cdk inhibitors. However, how the G2/M phase is regulated by Akt remains unclear. Here, we show that Akt counteracts the function of WEE1Hu. Inactivation of Akt by chemotherapeutic drugs or the phosphatidylinositide-3-OH kinase inhibitor LY294002 induced G2/M arrest together with the inhibitory phosphorylation of Cdc2. Because the increased Cdc2 phosphorylation was completely suppressed by wee1hu gene silencing, WEE1Hu was associated with G2/M arrest induced by Akt inactivation. Further analyses revealed that Akt directly bound to and phosphorylated WEE1Hu during the S to G2 phase. Serine-642 was identified as an Akt-dependent phosphorylation site. WEE1Hu kinase activity was not affected by serine-642 phosphorylation. We revealed that serine-642 phosphorylation promoted cytoplasmic localization of WEE1Hu. The nuclear-to-cytoplasmic translocation was mediated by phosphorylation-dependent WEE1Hu binding to 14-3-3θ but not 14-3-3β or -σ. These results indicate that Akt promotes G2/M cell cycle progression by inducing phosphorylation-dependent 14-3-3θ binding and cytoplasmic localization of WEE1Hu.

scholarly journals Cell Cycle-Dependence of Autophagic Activity and Inhibition of Autophagosome Formation at M Phase in Tobacco BY-2 Cells

2020 ◽  
Vol 21 (23) ◽  
pp. 9166
Author(s):  
Shigeru Hanamata ◽  
Takamitsu Kurusu ◽  
Kazuyuki Kuchitsu
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Plant Cells ◽  
Regulatory Mechanisms ◽  
Cdk Inhibitor ◽  
Autophagosome Formation ◽  
Cycle Progression ◽  
M Phase ◽  
Cell Cycle Dependence ◽  
Cycle Dependence

Autophagy is ubiquitous in eukaryotic cells and plays an essential role in stress adaptation and development by recycling nutrients and maintaining cellular homeostasis. However, the dynamics and regulatory mechanisms of autophagosome formation during the cell cycle in plant cells remain poorly elucidated. We here analyzed the number of autophagosomes during cell cycle progression in synchronized tobacco BY-2 cells expressing YFP-NtATG8a as a marker for the autophagosomes. Autophagosomes were abundant in the G2 and G1 phases of interphase, though they were much less abundant in the M and S phases. Autophagosomes drastically decreased during the G2/M transition, and the CDK inhibitor roscovitine inhibited the G2/M transition and the decrease in autophagosomes. Autophagosomes were rapidly increased by a proteasome inhibitor, MG-132. MG-132-induced autophagosome formation was also markedly lower in the M phases than during interphase. These results indicate that the activity of autophagosome formation is differently regulated at each cell cycle stage, which is strongly suppressed during mitosis.

scholarly journals The decision to enter mitosis: feedback and redundancy in the mitotic entry network

2009 ◽  
Vol 185 (2) ◽  
pp. 193-202 ◽  
Author(s):  
Arne Lindqvist ◽  
Verónica Rodríguez-Bravo ◽  
René H. Medema
Keyword(s):  
Cell Cycle ◽  
Normal Cell ◽  
Cell Cycle Progression ◽  
Feedback Loops ◽  
Cyclin B ◽  
Cycle Progression ◽  
Mitotic Entry ◽  
Different Levels ◽  
Normal Cell Cycle

The decision to enter mitosis is mediated by a network of proteins that regulate activation of the cyclin B–Cdk1 complex. Within this network, several positive feedback loops can amplify cyclin B–Cdk1 activation to ensure complete commitment to a mitotic state once the decision to enter mitosis has been made. However, evidence is accumulating that several components of the feedback loops are redundant for cyclin B–Cdk1 activation during normal cell division. Nonetheless, defined feedback loops become essential to promote mitotic entry when normal cell cycle progression is perturbed. Recent data has demonstrated that at least three Plk1-dependent feedback loops exist that enhance cyclin B–Cdk1 activation at different levels. In this review, we discuss the role of various feedback loops that regulate cyclin B–Cdk1 activation under different conditions, the timing of their activation, and the possible identity of the elusive trigger that controls mitotic entry in human cells.

Regulatory effect of thromboxane A2 on proliferation of vascular smooth muscle cells from rats

1992 ◽  
Vol 263 (5) ◽  
pp. H1331-H1338 ◽  
Author(s):  
T. Nagata ◽  
Y. Uehara ◽  
A. Numabe ◽  
T. Ishimitsu ◽  
N. Hirawa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Synthesis ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Cell Cycle Progression ◽  
Thromboxane A2 ◽  
Cycle Progression ◽  
M Phase ◽  
Rapid Transition

We investigated the regulatory effects of the vasoconstrictor thromboxane A2 on the proliferation of vascular smooth muscle cells (VSMC) from Wistar-Kyoto rats using 9,11-epithio-11,12-methano-thromboxane A2 (STA2), a stable analogue of thromboxane A2. STA2 dose dependently increased incorporation of [3H]thymidine into DNA in randomly cycling VSMC and significantly shortened the doubling time. Cell cycle analysis revealed that the increased cell cycle progression was primarily due to a rapid transition from the DNA synthetic (S) to the G2/mitotic (M) phase. Moreover, STA2 enhanced protein synthesis in VSMC during the G2/M phase, whereas the protein synthesis was unaffected in the G0/G1 period. In fact, STA2 prompted the cells in G2/M phase to synthesize actin, a major cytoskeleton protein. Conversely, inhibition of protein synthesis by puromycin retarded the transition from S to G2/M. In addition, depolymerization of the actin molecules by cytochalasin D offset the quick progression to the G2/M phase by STA2. These data indicate that thromboxane A2 stimulates the cell cycle progression in VSMC primarily through a rapid transition from S to G2/M. This enhanced progression is attributable partly to a rapid buildup of the cytoskeleton proteins during the G2/M period.

The Fluctuation of Telomere Repeat Binding Factor 1 during Cell Cycle and Its Localization in Telomerase-Positive and Negative Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4326-4326
Author(s):  
Jianping Lan ◽  
He Huang ◽  
Yuanyuan Zhu ◽  
Jie Sun
Keyword(s):  
Cell Cycle ◽  
Telomere Length ◽  
Hela Cells ◽  
Cell Cycle Progression ◽  
Promyelocytic Leukemia ◽  
Final Concentration ◽  
Cycle Progression ◽  
Telomere Repeat ◽  
Binding Factor ◽  
M Phase

Abstract Telomere is a nucleoprotein complex which caps the extreme ends of eukaryotic chromosomes. In human, telomere is composed of a tandem repeat array of TTAGGG hexanucleotide and bound to a set of specific proteins. These proteins function to maintain the integrity of chromosomes and genomic stability. Among these proteins, telomere repeat binding factor 1(TRF1) is the first telomere binding protein which was isolated by DNA affinity chromatography in 1995. TRF1 serves as a negative regulator of telomere length since TRF1 overexpression would elicit the shortening of telomere length in telomerase-positive cells. Meanwhile, overexpression of TRF1 would also induce the entry into mitosis and increase mitotic cells. These observation indicated TRF1 might participate in cell cycle regulation. However, the underlying mechanism in which TRF1 regulates the cell cycle and the endogenous level of TRF1 were not well-documented during cell cycle progression. To address these questions, we arrested HeLa cells at different phases by a combination of thymidine(5mM at final concentration) and nocodazole(20mM at final concentration) and detected the TRF1 levels by semi-quantitive Western Blotting assay. Cell cycle was verified by flow cytometry. Our results showed TRF1 level fluctuated coincided with cell cycle progression which reached the zenith at the M phase and went down to the nadir at G1/S point. Densitometry analysis demonstrated that the level of TRF1 at M phase was 3.9 times more than that at G1/S point(n=3, p<0.01). These results suggested that TRF1 might be essential for proper cell cycle progression and it was likely to take part in regulation of cell cycle chechpoint. TRF1 is also expressed in telomerase-negative cells. To further discriminate the different functions of TRF1 and decipher its protein-protein interaction network in telomerase-positive and negative cells, full-length TRF1 cDNA was amplified by PCR and subsequently subcloned into pEGFP-C2 vector to express TRF1 tagged by enhanced green fluorescent protein. This construct was then transiently transfected into telomerase-negative cells(WI38-2RA) and telomerase-positive cells(HeLa). Immunoflourescent staining was employed to check the localization of TRF1 in these two kinds of cells. Although in both cells, TRF1 was distributed in a speckled pattern in the nuclei, TRF1 did exclusively colocalize with promyelocytic leukemia(PML) nuclear body in WI38-2RA cells but not in HeLa cells. PML fused with RARα due to chromosome15,17 translocation which led to disassembly of PML nucleur body in acute promyelocytic leukemia. These preliminary results suggested that TRF1 might have the different regulating mechanism and interacting network.

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