scholarly journals Inhibition of centrosome protein assembly leads to p53-dependent exit from the cell cycle

2006 ◽  
Vol 174 (5) ◽  
pp. 625-630 ◽  
Author(s):  
Vlastimil Srsen ◽  
Nicole Gnadt ◽  
Alexander Dammermann ◽  
Andreas Merdes
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Human Fibroblasts ◽  
S Phase ◽  
Mitogen Activated Protein Kinase ◽  
Nuclear Antigen ◽  
Ki 67 ◽  
Mitogen Activated Protein ◽  
Centrosome Proteins ◽  
Centrosome Protein

Previous evidence has indicated that an intact centrosome is essential for cell cycle progress and that elimination of the centrosome or depletion of individual centrosome proteins prevents the entry into S phase. To investigate the molecular mechanisms of centrosome-dependent cell cycle progress, we performed RNA silencing experiments of two centrosome-associated proteins, pericentriolar material 1 (PCM-1) and pericentrin, in primary human fibroblasts. We found that cells depleted of PCM-1 or pericentrin show lower levels of markers for S phase and cell proliferation, including cyclin A, Ki-67, proliferating cell nuclear antigen, minichromosome maintenance deficient 3, and phosphorylated retinoblastoma protein. Also, the percentage of cells undergoing DNA replication was reduced by >50%. At the same time, levels of p53 and p21 increased in these cells, and cells were predisposed to undergo senescence. Conversely, depletion of centrosome proteins in cells lacking p53 did not cause any cell cycle arrest. Inhibition of p38 mitogen-activated protein kinase rescued cell cycle activity after centrosome protein depletion, indicating that p53 is activated by the p38 stress pathway.

scholarly journals Expression and modulation of p42/p44 MAPKs and cell cycle regulatory proteins in rat pancreas regeneration

1999 ◽  
Vol 277 (5) ◽  
pp. G953-G959 ◽  
Author(s):  
Jean Morisset ◽  
JoséCristobal Aliaga ◽  
Ezéquiel L. Calvo ◽  
Judith Bourassa ◽  
Nathalie Rivard
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Regulatory Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Cyclin Dependent Kinase ◽  
Mapk Activation ◽  
Pancreas Regeneration ◽  
Mitogen Activated Protein ◽  
Cell Cycle Regulatory Proteins

Pancreatic growth occurs after CCK, CCK-induced pancreatitis, and pancreatectomy; the mechanisms involved remain unknown. This study evaluates mitogen-activated protein kinase (MAPK) activation and expression of cell cycle regulatory proteins after pancreatectomy to understand the cellular and molecular mechanisms involved in pancreas regeneration. Rats were killed 1–12 days after pancreatectomy, and p42/p44 MAPK activation, expression of the cyclins D and E, cyclin-dependent kinase (Cdk)-2 activity, retinoblastoma protein (pRb) hyperphosphorylation, and expression of the cyclin kinase inhibitors p15, p21, and p27 were examined. Pancreatic remnants exhibited sustained p42/p44 MAPK activation within 8 h. Cyclins D1 and E showed maximal expression after 2 and 6 days, coinciding with maximal hyperphosphorylation of pRb and Cdk2 activity. The expression of p15 vanished after 12 h, p27 disappeared gradually, and p21 increased early. The p27 complexed with Cdk2 dissociated after 2 days, whereas p21 associated in a reverse fashion. In conclusion, sustained activation of p42/p44 MAPKs and Cdk2 along with overexpression of cyclins D1 and E and reduction of p15 and p27 cyclin inhibitors occurred early after pancreatectomy and are active factors involved in signaling that leads to pancreas regeneration.

scholarly journals Mouse model of testosterone-induced muscle fiber hypertrophy: involvement of p38 mitogen-activated protein kinase-mediated Notch signaling

2009 ◽  
Vol 201 (1) ◽  
pp. 129-139 ◽  
Author(s):  
Danielle Brown ◽  
Amiya P Sinha Hikim ◽  
Ekaterina L Kovacheva ◽  
Indrani Sinha-Hikim
Keyword(s):  
Protein Kinase ◽  
Mouse Model ◽  
Notch Signaling ◽  
P38 Mapk ◽  
Muscle Fiber ◽  
Molecular Mechanisms ◽  
Concomitant Administration ◽  
Mitogen Activated Protein Kinase ◽  
Nuclear Antigen ◽  
Mitogen Activated Protein

As a prerequisite for studies using mutant mice, we established a mouse model for investigating the molecular mechanisms by which testosterone (T) promotes muscle growth. Groups of six adult male mice (C57BL/6) received one of the following treatments: 1) vehicle (sterile distilled water; normal control) and 2) GnRH antagonist with empty (sham control) or 2 cm T- filled implant. Mice were killed 2, 6, and 8 weeks after treatment. T treatment for 8 weeks resulted in a significant (P<0.001) increase in fiber area of gastrocnemius muscles. T-induced fiber-hypertrophy was accompanied by up-regulation of the Notch ligand Delta 1 and activation of Notch signaling, as evidenced by increase in activated forms of Notch 1 and Notch 2. Consistent with this, we also observed an increase in the number of proliferating cell nuclear antigen (PCNA)-positive nuclei in muscles of T-treated mice, indicating that activation of Notch signaling enhanced cell proliferation. T supplementation not only triggered p38 mitogen-activated protein kinase (MAPK) activation but also concurrently inhibited c-Jun NH2-terminal kinase (JNK) activation within 2 weeks of treatment. Concomitant administration of SB203580, a p38 MAPK inhibitor, effectively blocked T-induced activation of Notch signaling and significantly (P<0.001) suppressed PCNA levels. Together, our results indicate that T induces muscle fiber hypertrophy through activation of Notch signaling and the inactivation of JNK together with the activation of p38 MAPK may be critical for T-induced activation of Notch signaling and, as a consequence, muscle fiber hypertrophy.

scholarly journals Atypical Mitogen-Activated Protein Kinase Phosphatase Implicated in Regulating Transition from Pre-S-Phase Asexual Intraerythrocytic Development of Plasmodium falciparum

2013 ◽  
Vol 12 (9) ◽  
pp. 1171-1178 ◽  
Author(s):  
Bharath Balu ◽  
Christopher Campbell ◽  
Jennifer Sedillo ◽  
Steven Maher ◽  
Naresh Singh ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Insertional Mutagenesis ◽  
S Phase ◽  
Mitogen Activated Protein Kinase ◽  
Phase Cell ◽  
Phosphatase Domain ◽  
Content Type ◽  
Mitogen Activated Protein

ABSTRACTIntraerythrocytic development of the human malaria parasitePlasmodium falciparumappears as a continuous flow through growth and proliferation. To develop a greater understanding of the critical regulatory events, we utilizedpiggyBacinsertional mutagenesis to randomly disrupt genes. Screening a collection ofpiggyBacmutants for slow growth, we isolated the attenuated parasite C9, which carried a single insertion disrupting the open reading frame (ORF) of PF3D7_1305500. This gene encodes a protein structurally similar to a mitogen-activated protein kinase (MAPK) phosphatase, except for two notable characteristics that alter the signature motif of the dual-specificity phosphatase domain, suggesting that it may be a low-activity phosphatase or pseudophosphatase. C9 parasites demonstrated a significantly lower growth rate with delayed entry into the S/M phase of the cell cycle, which follows the stage of maximum PF3D7_1305500 expression in intact parasites. Genetic complementation with the full-length PF3D7_1305500 rescued the wild-type phenotype of C9, validating the importance of the putative protein phosphatase PF3D7_1305500 as a regulator of pre-S-phase cell cycle progression inP. falciparum.

scholarly journals Regulation of DNA Replication Licensing and Re-Replication by Cdt1

2021 ◽  
Vol 22 (10) ◽  
pp. 5195
Author(s):  
Hui Zhang
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Genome Stability ◽  
E3 Ligase ◽  
S Phase ◽  
Replication Initiation ◽  
Nuclear Antigen ◽  
Repair Synthesis ◽  
Ubiquitin E3 Ligase

In eukaryotic cells, DNA replication licensing is precisely regulated to ensure that the initiation of genomic DNA replication in S phase occurs once and only once for each mitotic cell division. A key regulatory mechanism by which DNA re-replication is suppressed is the S phase-dependent proteolysis of Cdt1, an essential replication protein for licensing DNA replication origins by loading the Mcm2-7 replication helicase for DNA duplication in S phase. Cdt1 degradation is mediated by CRL4Cdt2 ubiquitin E3 ligase, which further requires Cdt1 binding to proliferating cell nuclear antigen (PCNA) through a PIP box domain in Cdt1 during DNA synthesis. Recent studies found that Cdt2, the specific subunit of CRL4Cdt2 ubiquitin E3 ligase that targets Cdt1 for degradation, also contains an evolutionarily conserved PIP box-like domain that mediates the interaction with PCNA. These findings suggest that the initiation and elongation of DNA replication or DNA damage-induced repair synthesis provide a novel mechanism by which Cdt1 and CRL4Cdt2 are both recruited onto the trimeric PCNA clamp encircling the replicating DNA strands to promote the interaction between Cdt1 and CRL4Cdt2. The proximity of PCNA-bound Cdt1 to CRL4Cdt2 facilitates the destruction of Cdt1 in response to DNA damage or after DNA replication initiation to prevent DNA re-replication in the cell cycle. CRL4Cdt2 ubiquitin E3 ligase may also regulate the degradation of other PIP box-containing proteins, such as CDK inhibitor p21 and histone methylase Set8, to regulate DNA replication licensing, cell cycle progression, DNA repair, and genome stability by directly interacting with PCNA during DNA replication and repair synthesis.

scholarly journals S-Phase Cell Cycle Arrest, Apoptosis, and Molecular Mechanisms of Aplasia Ras homolog Member I–Induced Human Ovarian Cancer SKOV3 Cell Lines

2014 ◽  
Vol 24 (4) ◽  
pp. 629-634 ◽  
Author(s):  
Qiaoying Zhu ◽  
Jianming Hu ◽  
Huijuan Meng ◽  
Yufei Shen ◽  
Jinhua Zhou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Molecular Mechanisms ◽  
Significant Inhibition ◽  
S Phase ◽  
Phase Cell ◽  
Cell Cycle Distribution ◽  
Human Ovarian Cancer ◽  
Skov3 Cell ◽  
Skov3 Cells

ObjectiveAplasia Ras homolog member I (ARHI) is associated with human ovarian cancer (HOC) growth and proliferation; however, the mechanisms are unclear. The purpose of this study was to investigateARHIeffects in HOC SKOV3 cells.MethodsWe transfected SKOV3 cells with PIRES2-EGFP-ARHI and measured growth inhibition rates, cell cycle distribution, apoptosis rates, and expression of P-STAT3 (phosphorylated signal transduction and activators of transcription 3) and P-ERK (phosphorylated extracellular signal regulated protein kinase).ResultsOur data showed significant inhibition of growth, significantly increased S-phase arrest and apoptosis rates, and reduction of P-STAT3 and P-ERK1/2 expression levels.ConclusionsWe propose the mechanism may involveARHI-induced phosphorylation of ERK1/2 and STAT3 protein kinases, thereby blocking proliferation signaling pathways, to induce HOC SKOV3 apoptosis.

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