The role of cell cycle control mechanisms in regulated and sustained cell proliferation

The cell cycle is the time a cell spends between two cell divisions. The cell cycle includes several parallel processes, all of which must be completed before a cell is mature for dividing. In the first place, all subcomponents (RNA, protein and membrane lipids) need to double in quantity and this occurs continuously through the cell cycle. Furthermore, the genome and some chromosomal proteins must double and this take place during a limited interval in the middle of the cell cycle (S-phase). On either side of the S-phase are two "gaps" which is called G1 and G2. When the cell has passed a point in the G-phase they are irreversibly programmed to progress through the remaining of the cell cycle and will undergo the next cell division. When a cell have passed a point in the G1 phase, approximately four hours after mitosis, a normal cell is in a state of indecision. During this phase (G1pm), the cell is affected by external factors, such as presence of certain growth factors and proximity to other cells to make a decision whether to continue toward S-phase or exit the cell cycle and enter a reversible resting stage-G0. G1pm phase is always of constant length (four hours), followed by a variable phase of G1 (G1ps) during which the cell builds its structural components with varying speed. A small cell spend a relatively longer time in G1ps than a larger one. The idea is that any size differences between cells will be adjusted before S-phase is initiated. Unlike normal cells, the transformed cells lack the ability to withdraw the G0 under suboptimal conditions. This article aims to summarize how normal and transformed cells relate to the G0-blocking and how individual factors determine the both cells relation to cell proliferation inhibition and "sustained proliferation."Cellcykeln benämns den tid som en cell tillbringar mellan två celldelningar. Cellcykeln innefattar flera parallella processer som alla måste slutföras innan en cell är mogen för delning. För det första måste alla cellens strukturella komponenter (RNA, proteiner och membranlipider) fördubblas och detta sker kontinuerligt genom cellcykeln. Dessutom måste arvsmassan och några av de kromosomala proteinerna fördubblas och detta sker under ett avgränsat intervall ungefär mitt i cellcykeln (S-fasen). På ömse sidor om S-fasen finns två ”gaps” som brukar kallas G1 och G2. När celler har passerat en punkt i G1-fasen är de oåterkalleligen programmerade för att progrediera genom återstoden av cellcykeln och kommer genomgå nästa celldelning. Ungefär fyra timmar efter mitos befinner sig normalcellen i ett stadium av obeslutsamhet. Under denna fas (G1pm) påverkas cellen av yttre faktorer som exempelvis tillgång till tillväxtfaktorer och närhet till andra celler att fatta ett beslut om den skall fortsätta mot S-fas eller utträda ur cellcykeln och inträda i ett reversibelt vilostadium – G0. G1pm-fasen är alltid av konstant längd (fyra timmar) och åtföljs av en variabel del, G1ps, under vilken cellen bygger upp sina strukturkomponenter med varierande hastighet. En liten cell tillbringar en relativt längre tid i G1ps än en större. Tanken är att alla storleksskillnader mellan celler skall vara utjämnade när S-fasen initieras. Till skillnad från normala celler saknar transformerade celler förmågan att utträda i G0 under suboptimala förhållanden. Denna artikel syftar till att sammanfatta hur normala och transformerade celler förhåller sig till G0-blockeringen samt hur enskilda faktorer styr de båda cellslagens förhållande till proliferationshämning och "sustained proliferation"

The effect of differential phosphorylation of YB-1 on apoptosis and cell cycle regulation

The purpose of this study was to investigate whether different phosphorylated forms of Y-box binding protein (YB-1) can affect the regulation of the cell cycle and/or apoptosis of cancer cells. Recent studies have suggested a key role for YB-1 in the regulation of cancer. Just like many other oncoproteins YB-1 is required for vital processes in the cell and hence it is not possible to apply YB-1 in a therapeutic role. Therefore, my aim was to elucidate whether or not one or more phosphorylated forms of YB-1 play a decisive role in apoptosis. Human colorectal cancer cells (HCT 116) were transfected with different phosphorylated forms of YB-1. These cells were subsequently analysed by flow cytometry in order to compare live/dead cells between the different mutants. The results from this study suggest that one of the mutants (S176A) plays a more important role when it comes to protecting the cells from apoptosis and hence contribute to promoting sustained proliferation. Moreover, in opposite to S176A, the results indicate that another mutant (S167A) seems to have a more important role protecting the cells from sustained proliferation.Syftet med denna studie var att undersöka huruvida olika fosforylerade former av Y-box binding protein-1 (YB-1) påverkar celldöd och/eller reglering av cell cykeln. Tidigare studier tyder på att YB-1 har en nyckelposition gällande reglering och uppkomst av cancer. Precis som med många andra onkoproteiner krävs YB-1 för många vitala processer i cellerna och därför kan inte behandling riktas generellt mot YB-1. Med denna studie hoppas jag därför kunna finna en eller flera olika fosforylerade former av YB-1 som har en mer eller mindre avgörande roll gällande apoptos. Detta för att behandling av cancer i framtiden då skulle kunna riktas mot enbart ett eller flera av dessa fosforyleringsställen. För att undersöka detta har humana colo-rektala cancerceller transfekterats med sex olika mutationer av YB-1, dessa har sedan analyserats med hjälp av flödescytometri för att jämföra levande/döda celler mellan de olika mutationerna

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Ungdomars, ledares och föräldrars upplevelser av 'KOMET för föräldrar till ungdomar 12-18 år'

Kometprogrammet började utvecklas 2001 och är en svensk variant av nordamerikanska manualbaserade föräldraträningsprogram. Varianten Komet 12-18 år riktar sig till föräldrar med utagerande ungdomar med syftet att bryta negativa beteendemönster genom att ändra föräldrarnas förhållningssätt till sina barn. Grundtankarna är hämtade från inlärningsteori, beteendeanalys, prevention och kognitiv beteendeterapi och bygger på evidensbaserad forskning. Syftet med studien är att bidra till utvecklingen av Komet 12-18 år och tillgodose ungdomsperspektivet med resultat från ungdomsintervjuer och –enkäter. Frågeställningen är om ungdomarna själva upplever någon förändring i sina föräldrars beteende och i så fall vilken efter genomgånget program. Ledarnas och föräldrarnas åsikter om programmet sammanfattas utifrån en enkätundersökning. Antalet deltagare blev lägre än väntat. Komets övergripande mål, att minska bråk och förbättra kommunikationen hemma, uppfylldes enligt de medverkande ungdomarna i genomsnitt men ungdomarna uttryckte sig försiktigare än både ledare och föräldrar angående förbättringen. Hos dem där förändring skett uppfattades den positivt och ungdomarna uppskattade ansträngningen från föräldrarna som främst mammorna stod för

What are analog bulletin boards used for today? : Analysing media uses, intermediality and technology affordances in Swedish bulletin board messages using a citizen science approach

Anslagstavlan: ForskarFredags Massexperiment 201

The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling

The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span