scholarly journals Cell Proliferation in Cutaneous Malignant Melanoma: Relationship with Neoplastic Progression

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
G. E. Piérard
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Malignant Melanoma ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Cutaneous Malignant Melanoma ◽  
Mitogen Activated Protein Kinase ◽  
Growth Fraction ◽  
Neoplastic Progression ◽  
Cell Cycle Phases

The establishment of the diagnosis of cutaneous malignant melanoma (CMM) always calls for histopathological confirmation. Further to the recognition of the CMM aspects, immunohistochemistry is helpful, in particular, in determining the size of the replicative compartment and the activity in each of the cell cycle phases (G1, S, G2, M). The involvement of cancer stem cells and transient amplifier cells in CMM genesis is beyond doubt. The proliferation activity is indicative of the neoplastic progression and is often related to the clinical growth rate of the neoplasm. It allows to distinguish high-risk CMM commonly showing a high growth rate, from those CMMs of lower malignancy associated with a more limited growth rate. The recruitment and progression of CMM cells in the cell cycle of proliferation depend on mitogen-activated protein kinase (MAPK) pathway and result from a loss of control normally involving a series of key regulatory cyclins. In addition, the apoptotic pathways potentially counteracting any excess in proliferative activity are out of the dependency of specific regulatory molecular mechanisms. Key molecular components involved in the deregulation of the growth fraction, the cell cycle phases of proliferation, and apoptosis are presently described in CMM.

scholarly journals The Role of Melanocortin 1 Receptor in Cutaneous Malignant Melanoma

2014 ◽  
Vol 16 (4) ◽  
pp. 421-428 ◽  
Author(s):  
Mary Beth Steck
Keyword(s):  
Malignant Melanoma ◽  
Mapk Pathway ◽  
The United States ◽  
Cutaneous Malignant Melanoma ◽  
Mitogen Activated Protein Kinase ◽  
Genomic Research ◽  
Melanocortin 1 Receptor ◽  
Red Hair ◽  
Increased Risk

Cutaneous malignant melanoma (CMM) is an epidemic cancer in the United States. Survival rates for invasive CMM have not increased in past decades despite numerous clinical trials and the effective use of various combinations of chemotherapy agents to treat other cancers. Recent research has investigated the role of melanocortin 1 receptor ( MC1R), a gene associated with red-hair phenotype in White individuals and with increased risk for developing CMM, in the mitogen-activated protein kinase (MAPK) pathway. This limited narrative review discusses the incidence, history, and risk factors for CMM. It explores familial CMM and provides a brief review of melanocyte development and melanogenesis. Histology of CMM and cytogenetic techniques used to identify CMM mutations is also discussed. The structure and function of MC1R is described, with particular attention to MC1R’s role in the MAPK pathway. Finally, the review touches on individualized therapy for CMM using genetic biomarkers and explores the promise of genomic research for finding effective treatments.

scholarly journals Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length

2017 ◽  
Author(s):  
Shixuan Liu ◽  
Miriam B. Ginzberg ◽  
Nish Patel ◽  
Marc Hild ◽  
Bosco Leung ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Size ◽  
P38 Mapk ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Small Cells ◽  
Animal Cells ◽  
Cycle Progression ◽  
Size Uniformity

AbstractAnimal cells within a tissue typically display a striking regularity in their size. To date, the molecular mechanisms that control this uniformity are still unknown. We have previously shown that size uniformity in animal cells is promoted, in part, by size-dependent regulation of G1 length. To identify the molecular mechanisms underlying this process, we performed a large-scale small molecule screen and found that the p38 MAPK pathway is involved in coordinating cell size and cell cycle progression. Small cells display higher p38 activity and spend more time in G1 than larger cells. Inhibition of p38 MAPK leads to loss of the compensatory G1 length extension in small cells, resulting in faster proliferation, smaller cell size and increased size heterogeneity. We propose a model wherein the p38 pathway responds to changes in cell size and regulates G1 exit accordingly, to increase cell size uniformity.One-sentence summaryThe p38 MAP kinase pathway coordinates cell growth and cell cycle progression by lengthening G1 in small cells, allowing them more time to grow before their next division.

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 Molecular Mechanisms of Liver Injury and Hepatocarcinogenesis: Focusing on the Role of Stress-Activated MAPK

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Hayato Nakagawa ◽  
Shin Maeda
Keyword(s):  
Liver Injury ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Effects ◽  
Wide Range ◽  
Mitogen Activated Protein ◽  
Compensatory Proliferation

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. Short-term prognosis of patients with HCC has improved recently due to advances in early diagnosis and treatment, but long-term prognosis is still unsatisfactory. Therefore, obtaining a further understanding of the molecular carcinogenic mechanisms and the unique pathogenic biology of HCC is important. The most characteristic process in hepatocarcinogenesis is underlying chronic liver injury, which leads to repeated cycles of hepatocyte death, inflammation, and compensatory proliferation and subsequently provides a mitogenic and mutagenic environment leading to the development of HCC. Recent in vivo studies have shown that the stress-activated mitogen-activated protein kinase (MAPK) cascade converging on c-Jun NH2-terminal kinase (JNK) and p38 plays a central role in these processes, and it has attracted considerable attention as a therapeutic target. However, JNK and p38 have complex functions and a wide range of cellular effects. In addition, crosstalk with each other and the nuclear factor-kappaB pathway further complicate these functions. A full understanding is essential to bring these observations into clinical settings. In this paper, we discuss the latest findings regarding the mechanisms of liver injury and hepatocarcinogenesis focusing on the role of the stress-activated MAPK pathway.

scholarly journals ROS-Mediated Apoptosis and Genotoxicity Induced by Palladium Nanoparticles in Human Skin Malignant Melanoma Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Saud Alarifi ◽  
Daoud Ali ◽  
Saad Alkahtani ◽  
Rafa S. Almeer
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Malignant Melanoma ◽  
Cell Cycle Arrest ◽  
Human Skin ◽  
Palladium Nanoparticles ◽  
Molecular Mechanisms ◽  
Time Dependent ◽  
Cycle Arrest ◽  
A375 Cells

The present work was designed to investigate the effect of palladium nanoparticles (PdNPs) on human skin malignant melanoma (A375) cells, for example, induction of apoptosis, cytotoxicity, and DNA damage. Diseases resulting from dermal exposure may have a significant impact on human health. There is a little study that has been reported on the toxic potential of PdNPs on A375. Cytotoxic potential of PdNPs (0, 5, 10, 20, and 40 μg/ml) was measured by tetrazolium bromide (MTT assay) and NRU assay in A375 cells. PdNPs elicited concentration and time-dependent cytotoxicity, and longer exposure period induced more cytotoxicity as measured by MTT and NRU assay. The molecular mechanisms of cytotoxicity through cell cycle arrest and apoptosis were investigated by AO (acridine orange)/EtBr (ethidium bromide) stain and flow cytometry. PdNPs not only inhibit proliferation of A375 cells in a dose- and time-dependent model but also induce apoptosis and cell cycle arrest at G2/M phase (before 12 h) and S phase (after 24 h). The induction of oxidative stress in A375 cells treated with above concentration PdNPs for 24 and 48 h increased ROS level; on the other hand, glutathione level was declined. Apoptosis and DNA damage was significantly increased after treatment of PdNPs. Considering all results, PdNPs showed cytotoxicity and genotoxic effect in A375 cells.

scholarly journals MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets

2008 ◽  
Vol 115 (7) ◽  
pp. 203-218 ◽  
Author(s):  
Anthony J. Muslin
Keyword(s):  
Molecular Mechanisms ◽  
Cardiovascular Health ◽  
Mapk Pathway ◽  
Science Research ◽  
Pharmacological Therapy ◽  
Model Systems ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.

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 Molecular Mechanisms Behind the Chemopreventive Effects of Anthocyanidins

2004 ◽  
Vol 2004 (5) ◽  
pp. 321-325 ◽  
Author(s):  
De-Xing Hou ◽  
Makoto Fujii ◽  
Norihiko Terahara ◽  
Makoto Yoshimoto
Keyword(s):  
Fruits And Vegetables ◽  
Molecular Mechanisms ◽  
Cell Transformation ◽  
Mapk Pathway ◽  
Animal Experiments ◽  
Cancer Chemoprevention ◽  
Mitogen Activated Protein Kinase ◽  
Blue Color ◽  
Activator Protein 1 ◽  
Mitogen Activated Protein

Anthocyanins are polyphenolic ring-based flavonoids, and are widespread in fruits and vegetables of red-blue color. Epidemiological investigations and animal experiments have indicated that anthocyanins may contribute to cancer chemoprevention. The studies on the mechanism have been done recently at molecular level. This review summarizes current molecular bases for anthocyanidins on several key steps involved in cancer chemoprevention: (i) inhibition of anthocyanidins in cell transformation through targeting mitogen-activated protein kinase (MAPK) pathway and activator protein 1 (AP-1) factor; (ii) suppression of anthocyanidins in inflammation and carcinogenesis through targeting nuclear factorkappaB (NF-κB) pathway andcyclooxygenase2 (COX-2) gene; (iii) apoptotic induction of cancer cells by anthocyanidins through reactive oxygen species (ROS) / c-Jun NH2-terminal kinase (JNK)-mediated caspase activation. These data provide a first molecular view of anthocyanidins contributing to cancer chemoprevention.

scholarly journals Transcriptional Coregulation by the Cell Integrity Mitogen-Activated Protein Kinase Slt2 and the Cell Cycle Regulator Swi4

2001 ◽  
Vol 21 (19) ◽  
pp. 6515-6528 ◽  
Author(s):  
Kristin Baetz ◽  
Jason Moffat ◽  
Jennifer Haynes ◽  
Michael Chang ◽  
Brenda Andrews
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Wall ◽  
Transcription Factor ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Regulatory Subunit ◽  
Cell Integrity ◽  
Mitogen Activated Protein

ABSTRACT In Saccharomyces cerevisiae, the heterodimeric transcription factor SBF (for SCB binding factor) is composed of Swi4 and Swi6 and activates gene expression at the G1/S-phase transition of the mitotic cell cycle. Cell cycle commitment is associated not only with major alterations in gene expression but also with highly polarized cell growth; the mitogen-activated protein kinase (MAPK) Slt2 is required to maintain cell wall integrity during periods of polarized growth and cell wall stress. We describe experiments aimed at defining the regulatory pathway involving the cell cycle transcription factor SBF and Slt2-MAPK. Gene expression assays and chromatin immunoprecipitation experiments revealed Slt2-dependent recruitment of SBF to the promoters of the G1 cyclinsPCL1 and PCL2 after activation of the Slt2-MAPK pathway. We performed DNA microarray analysis and identified other genes whose expression was reduced in both SLT2and SWI4 deletion strains. Genes that are sensitive to both Slt2 and Swi4 appear to be uniquely regulated and reveal a role for Swi4, the DNA-binding component of SBF, which is independent of the regulatory subunit Swi6. Some of the Swi4- and Slt2-dependent genes do not require Swi6 for either their expression or for Swi4 localization to their promoters. Consistent with these results, we found a direct interaction between Swi4 and Slt2. Our results establish a new Slt2-dependent mode of Swi4 regulation and suggest roles for Swi4 beyond its prominent role in controlling cell cycle transcription.

scholarly journals Nucleolar stress causes the entry into replicative senescence in budding yeast

2018 ◽  
Author(s):  
Sandrine Morlot ◽  
Song Jia ◽  
Isabelle Léger-Silvestre ◽  
Audrey Matifas ◽  
Olivier Gadal ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Molecular Mechanisms ◽  
Replicative Senescence ◽  
Cellular Aging ◽  
Daughter Cells ◽  
Nucleolar Stress ◽  
Unique Framework ◽  
Massive Accumulation

SummaryThe accumulation of Extrachromosomal rDNA Circles (ERCs) and their asymmetric segregation upon division have been hypothesized to be responsible for replicative senescence in mother yeasts and rejuvenation in daughter cells. However, it remains unclear by which molecular mechanisms ERCs would trigger the irreversible cell cycle slow-down leading to cell death. We show that ERCs accumulation is concomitant with a nucleolar stress, characterized by a massive accumulation of pre-rRNAs in the nucleolus, leading to a loss of nucleus-to-cytoplasm ratio, decreased growth rate and cell-cycle slow-down. This nucleolar stress, observed in old mothers, is not inherited by rejuvenated daughters. Unlike WT, in the long-lived mutant fob1∆, a majority of cells is devoid of nucleolar stress and does not experience replicative senescence before death. Our study provides a unique framework to order the successive steps that govern the transition to replicative senescence and highlights the causal role of nucleolar stress in cellular aging.

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