Wig-1: A p53 target that regulates the mRNA of p53 and Myc - and more?

Wig-1 is a transcriptional target of the tumor suppressor p53. p53 is activated by cellular stress and can induce a wide variety of responses. Some like apoptosis follow upon severe damage, while milder damage results in outcomes such as cell cycle arrest and DNA repair. Yet other p53 functions rely on physiological p53 levels. p53 mainly exerts its functions through inducing the transcription of target genes, hence in order to understand the function of p53 one must understand the function of these targets. Wig-1 was identified as a p53 target more than ten years ago, and was found to be a double stranded RNA binding protein. Apart from that, however, its function has remained elusive. In this work we demonstrate that Wig-1 regulates mRNA stability through binding to so-called AU-rich elements in 3 UTRs, and we identify p53 as well as N- and c-Myc as its targets. We also report that Wig-1 knockout causes early embryonic lethality in mice, probably due to dysregulation of Wig-1 targets such as Myc. Thus we show that p53, through Wig-1, can activate Myc and possibly other prosurvival targets. This activation may represent a way of facilitating for cells to recommence cycling after a repaired damage. Simultaneously, increased Wig-1 sensitizes the cell to any remaining damage by also stabilizing the p53 mRNA. In conclusion, we have found that the p53 target Wig-1 regulates mRNA stability through AU-rich elements. We propose a novel mechanism by which p53, through Wig-1, can tweak the cell milieu toward survival

The p53 target protein Wig-1 binds hnRNP A2/B1 and RNA Helicase A via RNA

AbstractThe p53-induced Wig-1 gene encodes a double stranded RNA-binding zinc finger protein. We generated Saos-2 osteosarcoma cells expressing tetracycline-inducible Flag-tagged human Wig-1. Induction of Wig-1 expression by doxycycline inhibited cell growth in a long-term assay but did not cause any changes in cell cycle distribution nor increased fraction of apoptotic cells. Using co-immunoprecipitation and mass spectrometry, we identified two Wig-1-binding proteins, hnRNP A2/B1 and RNA Helicase A, both of which are involved in RNA processing. The binding was dependent on the presence of RNA. Our results establish a link between the p53 tumor suppressor and RNA processing via hnRNPA2/B1 and RNA Helicase A.Structured summaryMINT-6542926, MINT-6542899:WIG1 (uniprotkb:Q9HA38) physically interacts (MI:0218) with hnRNP A2/B1 (uniprotkb:P22626) by anti bait coimmunoprecipitation (MI:0006)MINT-6542945:RHA (uniprotkb:Q08211) physically interacts (MI:0218) with hnRNP A2/B1 (uniprotkb:P22626) by anti bait coimmunoprecipitation (MI:0006)MINT-6542918, MINT-6542891:WIG1 (uniprotkb:Q9HA38) physically interacts (MI:0218) with RHA (uniprotkb:Q08211) by anti bait coimmunoprecipitation (MI:0006)MINT-6542867:WIG1 (uniprotkb:Q9HA38) physically interacts (MI:0218) with RHA (uniprotkb:Q08211) by anti tag coimmunoprecipitation (MI:0007)MINT-6542879:WIG1 (uniprotkb:Q9HA38) physically interacts (MI:0218) with hnRNP A2/B1(uniprotkb:P22626) by anti tag coimmunoprecipitation (MI:0007

Burn injuries in children: admissions at Landspitali University Hospital in Iceland 2000-2008

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn Skoða/Opna(view/open)BACKGROUND: Causes of burn injuries in children are universally associated with social and environmental factors. Epidemiological studies are therefore important in identifying risk factors and for planning preventive interventions. METHODS: Children younger than 18 years with skin burns who were treated as inpatients at Landspitali University Hospital over a 9-year period, 2000 and 2008, were included in this retrospective descriptive study. Data was collected from medical records. RESULTS: Of 149 children included in the study 41.6% were four years old or younger. The average annual incidence of hospital admissions was 21/100,000. Cold water as first aid was applied in 78% of cases. Half of the accidents occurred in the home where a close family member was the caretaker. Risk factors were identified in 11.4% of the accidents and abuse or neglect was suspected in 3.4% of cases. Scalds were the most common type of burn injury (50.3%) followed by burns caused by fire (20.4%) including gas or petrol (14.9%) and fireworks (17.6%). The most common source of scalds was exposure to hot water from hot water mains (12,9%) and heated water (12,9%). The mean time from emergency room admission to the paediatric ward was two hours and 22 minutes. The mean length of stay was 13 days; median 9 days (range 1-97). CONCLUSION: Incidence of hospital admissions for burn injury has decreased when compared with earlier Icelandic studies. Children four years and younger and boys between 13-16 years old are most at risk for burn injuries. Stronger preventive measures as well as better documentation of burn accidents are imperative.Tilgangur: Að afla upplýsinga um brunaslys barna sem lögðust inn á Landspítala á níu ára tímabili, meta hvort efla þurfi forvarnir og endurskoða ákveðna þætti í meðferð. Aðferðir: Í þessari afturskyggnu lýsandi rannsókn var upplýsingum safnað úr sjúkraskrám um börn yngri en átján ára sem dvöldu lengur en≥ sólarhring á Landspítala vegna brunaáverka á húð á árunum 2000-2008. Niðurstöður: Af 149 börnum voru 108 drengir og 41 stúlka. Meðalfjöldi innlagna á ári var 16,5 eða 21/100 000. Brunaslys voru algengust hjá fjögurra ára og yngri (41,6%) og í aldurshópnum 13-16 ára (45,7%). Hjá meirihlutanum (81%) var útbreiðsla áverka £10% af líkamsyfirborði. Helmingur slysa varð inni á heimili. Sár voru kæld á vettvangi í 78% tilvika. Áhættuþættir voru til staðar hjá 11,4% barna og hjá 3,4% barna var grunur um vanrækslu eða ofbeldi. Helstu brunavaldar voru heitt vatn og aðrir heitir vökvar (50,3%), þar af neysluvatn í 12,9% tilvika, eldur í 20,4% tilvika, þar af gas eða bensín hjá 14,9% barna, og skoteldar (17,6%). Meðaltími frá komu á bráðamóttöku að innlögn á barnadeild var 142 mínútur, (25-333). Meðallegutími var 13 dagar, miðgildið níu dagar (1-97) að meðtöldum sex dögum á gjörgæsludeild, miðgildið tveir dagar (1- 48) . Ályktun:Innlögnum vegna brunaáverka hefur fækkað. Algengustu brunavaldar eru heitt vatn, heitir vökvar, eldur og skoteldar. Flest eru slysin hjá börnum ≤yngri en fjögurra ára og hjá drengjum 13-16 ára. Mikilvægt er að auka öryggi barna á heimilum og beina forvörnum að áhættuhópum. Vanda þarf fyrsta mat á útbreiðslu sára og greina þætti sem hafa áhrif á dvalartíma á bráðamóttöku og legudeild. Bæta þarf skráningu í sjúkraskrá

Calcium signaling and transcription: elongation, DoGs, and eRNAs

The calcium ion (Ca2+) is a key intracellular signaling molecule with far-reaching effects on many cellular processes. One of the most important Ca2+ regulated processes is transcription. A body of literature describes the effect of Ca2+ signaling on transcription initiation as occurring mainly through activation of gene-specific transcription factors by Ca2+-induced signaling cascades. However, the reach of Ca2+ extends far beyond the first step of transcription. In fact, Ca2+ can regulate all phases of transcription, with additional effects on transcription-associated events such as alternative splicing. Importantly, Ca2+ signaling mediates reduced transcription termination in response to certain stress conditions. This reduction allows readthrough transcription, generating a highly inducible and diverse class of downstream of gene containing transcripts (DoGs) that we have recently described

Perinatal essential fatty acid deficiency in mice: effects on metabolism and behaviour

Maternal nutritional status during pregnancy and lactation influences the health of the adult offspring and an adequate supply of essential fatty acids is important for foetal and postnatal growth and development. The overall aim of this thesis was to study short- and long-term effects of perinatal essential fatty acid deficiency in mice on metabolism and behaviour. An essential fatty acid deficient (EFAD) diet or a control diet was given to mouse dams during the latter half of pregnancy (prenatal EFAD) or 4 days before delivery and throughout lactation (postnatal EFAD). The pups were weaned to standard diet (STD) and were later subdivided into two groups, receiving high fat diet (HFD) or STD. Body weight, body composition, food intake, energy expenditure, glucose tolerance and plasma leptin were analyzed in the adult offspring in both the prenatal and postnatal EFAD studies. In the postnatal EFAD males, lipids, fatty acids and gene expression in the liver and plasma lipids were also analyzed. In addition, the short- and long-term effects of postnatal EFAD on brain fatty acids together with long-term effects on behaviour were studied in the female mice. Prenatal EFAD resulted in sex-specific long-term effects with lower body weight and leptin levels in the adult female mice and higher fasting glucose and lower insulin sensitivity in the adult male mice compared to controls. Mice of both gender with postnatal EFAD exhibited lower body weight, reduced body fat and lower plasma leptin and insulin concentrations compared to controls. The postnatal EFAD mice were resistant to HFD-induced obesity, liver steatosis and hypercholesterolemia during adult life. Finally, postnatal EFAD had long-term effects associated with decreased anxiety and increased risk behaviour in adult female mice. In conclusion, these results suggest that both the sex and the period of exposure (prenatal or postnatal) modulate the long-term effects of EFAD in mice

Caution needs to be taken when assigning transcription start sites to ends of protein-coding genes: a rebuttal

Abstract Naturally occurring stress-induced transcriptional readthrough is a recently discovered phenomenon, in which stress conditions lead to dramatic induction of long transcripts as a result of transcription termination failure. In 2015, we reported the induction of such downstream of gene (DoG) containing transcripts upon osmotic stress in human cells, while others observed similar transcripts in virus-infected and cancer cells. Using the rigorous methodology Cap-Seq, we demonstrated that DoGs result from transcriptional readthrough, not de novo initiation. More recently, we presented a genome-wide comparison of NIH3T3 mouse cells subjected to osmotic, heat, and oxidative stress and concluded that massive induction of transcriptional readthrough is a hallmark of the mammalian stress response. In their recent letter, Huang and Liu in contrast claim that DoG transcripts result from novel transcription initiation near the ends of genes. Their conclusions rest on analyses of a publicly available transcription start site (TSS-Seq) dataset from unstressed NIH3T3 cells. Here, we present evidence that this dataset identifies not only true transcription start sites, TSSs, but also 5′-ends of numerous snoRNAs, which are generally processed from introns in mammalian cells. We show that failure to recognize these erroneous assignments in the TSS-Seq dataset, as well as ignoring published Cap-Seq data on TSS mapping during osmotic stress, have led to misinterpretation by Huang and Liu. We conclude that, contrary to the claims made by Huang and Liu, TSS-Seq reads near gene ends cannot explain the existence of DoGs, nor their stress-mediated induction. Rather it is, as we originally demonstrated, transcriptional readthrough that leads to the formation of DoGs

Prenatal essential fatty acid deficiency in mice results in long-term gender-specific effects on body weight and glucose metabolism

Essential fatty acids are important for normal growth and development in early life. However, the long-term effects of prenatal essential fatty acid deficiency (EFAD) on the adult metabolism remain to be determined. The aim of this study was to investigate the effects of an EFAD diet given to mice during late gestation on body weight and body composition, and metabolism in the adult offspring. Pregnant dams were given an EFAD or a control diet during the last 10 days of gestation. After delivery, all mice were fed normal chow and the body weight of the offspring was measured weekly. Furthermore, food intake, energy expenditure and intraperitoneal glucose tolera-nce were analysed in the adult offspring in addition to body composition (analysed by dual-energy X-ray absorptiometry), plasma levels of leptin, triglycerides and cholesterol. The body weight was lower in the EFAD offspring as compared to the controls during the first 4 weeks of age, and remained lower in the females throughout the study. Lean body mass and plasma leptin levels were also lower in the female EFAD offspring as compared to the controls. Male EFAD offspring were found to have higher fasting glucose and insulin levels as well as higher insulin levels during the glucose tolerance test compared to the controls. However, no differences were found in blood lipids, food intake or energy expenditure between EFAD and control mice of either gender. These results demonstrate that an EFAD diet given during the last 10 days of gestation results in long-term gender-specific effects on body weight and insulin sensitivity in the adult offspring