Orbital mucosa-associated lymphoid tissue (MALT) lymphoma as the initial presentation in patients with hepatitis C virus infection.

Hepatitis C virus infection may be implicated in 12.7% of ocular adnexal marginal zone lymphomas. We present the first case of an orbital-systemic mucosa-associated lymphoid tissue lymphoma that responded to hepatitis C virus medical treatment. A 62-year-old male with a right-sided orbital mass was diagnosed with stage IIA orbital marginal zone lymphoma in addition to hepatitis C virus infection based on clinical, imaging, laboratory, and histological examinations. The systemic and orbital responses were achieved 1 year after undergoing hepatitis C virus treatment with glecaprevir/pibrentasvir. The association between the hepatitis C virus infection and orbital-systemic mucosa-associated lymphoid tissue lymphoma is relevant. Accordingly, patients with orbital mucosa-associated lymphoid tissue lymphoma should be assessed for hepatitis C virus seroreactivity for therapeutic and prognostic purposes.

Orbital mucosa-associated lymphoid tissue (MALT) lymphoma as the initial presentation in patients with hepatitis C virus infection

ABSTRACT Hepatitis C virus infection may be implicated in 12.7% of ocular adnexal marginal zone lymphomas. We present the first case of an orbital-systemic mucosa-associated lymphoid tissue lymphoma that responded to hepatitis C virus medical treatment. A 62-year-old male with a right-sided orbital mass was diagnosed with stage IIA orbital marginal zone lymphoma in addition to hepatitis C virus infection based on clinical, imaging, laboratory, and histological examinations. The systemic and orbital responses were achieved 1 year after undergoing hepatitis C virus treatment with glecaprevir/pibrentasvir. The association between the hepatitis C virus infection and orbital-systemic mucosa-associated lymphoid tissue lymphoma is relevant. Accordingly, patients with orbital mucosa-associated lymphoid tissue lymphoma should be assessed for hepatitis C virus seroreactivity for therapeutic and prognostic purposes.

Regulatory CDH4 Genetic Variants Associate With Risk to Develop Capecitabine-Induced Hand-Foot Syndrome.

Capecitabine-induced hand-foot syndrome (CiHFS) is a common dermatological adverse reaction affecting around 30% of patients with capecitabine-treated cancer, and the main cause of dose reductions and chemotherapy delays. To identify novel genetic factors associated with CiHFS in patients with cancer, we carried out an extreme-phenotype genomewide association study in 166 patients with breast and colorectal capecitabine-treated cancer with replication in a second cohort of 85 patients. We discovered and replicated a cluster of four highly correlated single-nucleotide polymorphisms associated with susceptibility to CiHFS at 20q13.33 locus (top hit = rs6129058, hazard ratio = 2.40, 95% confidence interval = 1.78-3.20; P = 1.2 × 10-8 ). Using circular chromosome conformation capture sequencing, we identified a chromatin contact between the locus containing the risk alleles and the promoter of CDH4, located 90 kilobases away. The risk haplotype was associated with decreased levels of CDH4 mRNA and the protein it encodes, R-cadherin (RCAD), which mainly localizes in the granular layer of the epidermis. In human keratinocytes, CDH4 downregulation resulted in reduced expression of involucrin, a protein of the cornified envelope, an essential structure for skin barrier function. Immunohistochemical analyses revealed that skin from patients with severe CiHFS exhibited low levels of RCAD and involucrin before capecitabine treatment. Our results uncover a novel mechanism underlying individual genetic susceptibility to CiHFS with implications for clinically relevant risk prediction.

Specialized functions of cohesins STAG1 and STAG2 in 3D genome architecture.

Cohesin is a complex conserved in evolution that entraps DNA. Originally identified for its role in sister chromatid cohesion, it is currently considered a key player in 3D genome organization. In vertebrates, two paralog genes encode two versions of the SA/STAG subunit of cohesin, STAG1 and STAG2. While the existence of two variant complexes has been largely ignored in many cohesin studies, the high frequency of STAG2 mutations in cancer has stirred up the interest in dissecting the unique properties that the STAG proteins confer on cohesin. In this review, we summarize recent progress in our understanding of the functional specificity of cohesin-STAG1 and cohesin-STAG2 with particular emphasis on their contributions to genome organization and gene regulation.

Índice leuco-glucémico como predictor de mortalidad en la insuficiencia cardiaca / Leuko-glycaemic index as mortality predictor in heart failure

RESUMEN Introducción: actualmente en la medicina de emergencia se buscan marcadores de riesgo para predecir resultados. Los índices pronósticos han sido ampliamente aplicados en la insuficiencia cardiaca con resultados variables. Objetivo: probar al índice leuco-glucémico como marcador de mortalidad en la insuficiencia cardiaca, así como calcular el valor de corte. Materiales y métodos: se realizó un estudio analítico longitudinal retrospectivo, con todos los pacientes ingresados en la Unidad de Cuidados Intensivos Emergentes por Insuficiencia Cardiaca descompensada del Hospital Militar Dr. Carlos J. Finlay, de enero de 2017 hasta junio de 2017 que cumplieron con los criterios de inclusión y exclusión. Resultados: la media de la edad fue de 79 ±12 años. La mortalidad global estuvo en el orden de 29 %. En la muestra existieron 17 mujeres y 14 hombres. El índice de error en la predicción de la mortalidad por el ILG es de solo el 5,6 %. La curva ROC área bajo la curva 0,995 IC 95 % (0,979-1) se evidencia un punto de corte en 1934, es decir que el resultado del índice leuco-glucémico mayor de este valor tiene una sensibilidad del 88,9 % y una especificidad del 100 % para detectar a los posibles occisos. Conclusiones: el índice leuco-glucémico puede ser un elemento a tener en cuenta en el pronóstico de estos. Tiene una elevada sensibilidad y especificidad en la detección de pacientes con riesgo de morir por insuficiencia cardiaca (AU).

ABSTRACT Introduction: currently, risk factors are looked for to predict results in emergency medicine. The prognosis indexes have been widely applied to heart failure, with uneven results. Objectives: to test the leuko-glycaemic index as mortality indicator in heart failure, as well as to calculate the cut-off value. Material and methods: a retrospective, longitudinal analytical study was carried out with all the patients who entered the Emergency Intensive Care Unit of the Military Hospital "Carlos J. Finlay" because of decompensated heart failure, from January 2017 until June 2017, and fulfilled the inclusion and exclusion criteria. Results: the average age was 79±12 years. Global mortality was around 29 %. The sample was composed by 17 women and 14 men. The error rate in mortality prediction by leuko-glycaemic index is only 5.6 %. The area below the ROC curve is 0,995; IC 95 % (0,979;1); it is evidenced a cut-off point in 1934; therefore, leuko-glycaemic index result higher than this value has a sensibility of 88.9 % and a specificity of 100 % to detect possible deceases. Conclusions: leuko-glycaemic index may be an element to take into account in this prognosis. It has a high sensibility and specificity in detecting patients at risk of dying due to heart failure (AU).

Persistent accumulation of unrepaired DNA damage in rat cortical neurons: nuclear organization and ChIP-seq analysis of damaged DNA.

Neurons are highly vulnerable to DNA damage induced by genotoxic agents such as topoisomerase activity, oxidative stress, ionizing radiation (IR) and chemotherapeutic drugs. To avert the detrimental effects of DNA lesions in genome stability, transcription and apoptosis, neurons activate robust DNA repair mechanisms. However, defective DNA repair with accumulation of unrepaired DNA are at the basis of brain ageing and several neurodegenerative diseases. Understanding the mechanisms by which neurons tolerate DNA damage accumulation as well as defining the genomic regions that are more vulnerable to DNA damage or refractory to DNA repair and therefore constitute potential targets in neurodegenerative diseases are essential issues in the field. In this work we investigated the nuclear topography and organization together with the genome-wide distribution of unrepaired DNA in rat cortical neurons 15 days upon IR. About 5% of non-irradiated and 55% of irradiated cells accumulate unrepaired DNA within persistent DNA damage foci (PDDF) of chromatin. These PDDF are featured by persistent activation of DNA damage/repair signaling, lack of transcription and localization in repressive nuclear microenvironments. Interestingly, the chromatin insulator CTCF is concentrated at the PDDF boundaries, likely contributing to isolate unrepaired DNA from intact transcriptionally active chromatin. By confining damaged DNA, PDDF would help preserving genomic integrity and preventing the production of aberrant proteins encoded by damaged genes.ChIP-seq analysis of genome-wide γH2AX distribution revealed a number of genomic regions enriched in γH2AX signal in IR-treated cortical neurons. Some of these regions are in close proximity to genes encoding essential proteins for neuronal functions and human neurodegenerative disorders such as epm2a (Lafora disease), serpini1 (familial encephalopathy with neuroserpin inclusion bodies) and il1rpl1 (mental retardation, X-linked 21). Persistent γH2AX signal close to those regions suggests that nearby genes could be either more vulnerable to DNA damage or more refractory to DNA repair.

Distinct roles of cohesin-SA1 and cohesin-SA2 in 3D chromosome organization.

Two variant cohesin complexes containing SMC1, SMC3, RAD21 and either SA1 (also known as STAG1) or SA2 (also known as STAG2) are present in all cell types. We report here their genomic distribution and specific contributions to genome organization in human cells. Although both variants are found at CCCTC-binding factor (CTCF) sites, a distinct population of the SA2-containing cohesin complexes (hereafter referred to as cohesin-SA2) localize to enhancers lacking CTCF, are linked to tissue-specific transcription and cannot be replaced by the SA1-containing cohesin complex (cohesin-SA1) when SA2 is absent, a condition that has been observed in several tumors. Downregulation of each of these variants has different consequences for gene expression and genome architecture. Our results suggest that cohesin-SA1 preferentially contributes to the stabilization of topologically associating domain boundaries together with CTCF, whereas cohesin-SA2 promotes cell-type-specific contacts between enhancers and promoters independently of CTCF. Loss of cohesin-SA2 rewires local chromatin contacts and alters gene expression. These findings provide insights into how cohesin mediates chromosome folding and establish a novel framework to address the consequences of mutations in cohesin genes in cancer.

Incidence, Causes, and Impact of In-Hospital Infections After Transcatheter Aortic Valve Implantation.

In-hospital infections (IHI) are one of the most common and serious problems after invasive procedures. Transcatheter aortic valve implantation (TAVI) is an increasingly used alternative to surgery in patients with severe symptomatic aortic stenosis. The aim of this study was to determine the incidence, origin, risk factors, and clinical outcomes of IHI after TAVI. A total of 303 consecutive patients with severe aortic stenosis who underwent transfemoral TAVI were included and followed during a median time of 21 months. We examined the occurrence, types, origin, and timing of infections during hospital stay as well as short- and long-term clinical outcomes according to the occurrence of IHI. A total of 51 patients (17%; 62 infectious episodes) experienced IHI after TAVI. Respiratory and urinary tract infections were the most frequent type of infections (44% and 34%, respectively), followed by surgical site infection (8%) and bloodstream infection (5%). Positive cultures were obtained in 74% of the samples, of which 65% were gram-negative bacilli. Modifiable factors such as bleeding (p = 0.005) and length of coronary care unit stay (p <0.001) were independently associated with an increased infection risk. Patients with IHI had a longer hospital stay (14 vs 6 days, p <0.001), an increased mortality (hazard ratio 2.48, 95% CI 1.45 to 4.23) and readmission rate (hazard ratio 2.0, 95% CI 1.27 to 3.14) during the follow-up. In conclusion, IHI is a frequent complication after TAVI with a significant impact on short- and long-term clinical outcomes. The most important risk factors associated with the development of this complication were modifiable periprocedural aspects. These results underline the importance to implement specific preventive strategies to reduce in-hospital-acquired infections after TAVI.

Aplicación de dos modos ventilatorios en colecistectomía laparoscópica / Application of two modes of ventilation in laparoscopic cholecystectomy

Fundamento: el mantenimiento de la oxigenación es un problema frecuente en los pacientes sometidos a colecistectomía laparoscópica. No existen guías específicas para aplicar los modos ventilatorios en este tipo de operación. Objetivo: comparar los modos ventilatorios volumen control y presión control en pacientes sometidos a colecistectomía laparoscópica. Métodos: se desarrolló un estudio analítico longitudinal prospectivo. La muestra estuvo conformada por 18 pacientes de clasificación ASA I and II, programados para realizarle colecistectomía laparoscópica en el Hospital Militar Docente Dr. Octavio de la Concepción y de la Pedraja de Camagüey. Al comenzar, todos los pacientes recibieron ventilación ciclada por volumen. Luego de 20 minutos de realizar el neumoperitoneo todos recibieron ventilación ciclada por presión. Las variables estudiadas fueron saturación de O2, presión pico y presión meseta, frecuencia respiratoria y parámetros hemodinámicos. Resultados: la presión pico no tuvo significación estadística. La presión meseta presentó diferencias significativas. La frecuencia respiratoria aumentó más en la modalidad ciclada por presión que en la modalidad ciclada por volumen, sin significación estadística. La oxigenación presentó los mismos valores en ambos modos. Los parámetros hemodinámicos fueron similares pero con mayor dispersión en el modo ciclado por volumen. La frecuencia cardiaca fue similar en ambos modos de ventilación. La presión arterial media no tuvo significación estadística. Conclusiones: solo existió diferencia entre los modos en la presión meseta.

Background: the maintenance of oxygenation is a frequent problem in patients who undergo a laparoscopic cholecystectomy. There are not specific guides for applying the modes of ventilation in this type of surgery. Objective: to compare two modes of ventilation, volume-controlled ventilation and pressure-controlled ventilation in patients who undergo a laparoscopic cholecystectomy. Methods: an analytical, longitudinal study was conducted. The sample was composed of 18 patients of ASA physical status I and II, scheduled for a laparoscopic cholecystectomy in Dr Octavio de la Concepción y de la Pedraja Military Teaching Hospital, Camaguey. At first, all the patients received volume-controlled ventilation. Twenty minutes later, when the pneumoperitoneum was administered, all of them received pressure-controlled ventilation. The studied variables were O2 saturation, peak pressure, plateau pressure, respiration rate and hemodynamic parameters. Results: there was not statistical significance regarding the peak pressure. Plateau pressure presented significant differences. Respiration rate increased more with pressure-controlled ventilation than with volume-controlled ventilation, without statistical significance. Oxygenation had the same values in both modes of ventilation. The hemodynamic parameters were similar, showing more dispersion with volume-controlled ventilation. Heart rate was similar in both modes of ventilation. There was not statistical significance regarding the mean arterial pressure. Conclusion: there was difference between both modes of ventilation only regarding the plateau pressure.

The contribution of cohesin-SA1 to gene expression and chromatin architecture in two murine tissues.

Cohesin, which in somatic vertebrate cells consists of SMC1, SMC3, RAD21 and either SA1 or SA2, mediates higher-order chromatin organization. To determine how cohesin contributes to the establishment of tissue-specific transcriptional programs, we compared genome-wide cohesin distribution, gene expression and chromatin architecture in cerebral cortex and pancreas from adult mice. More than one third of cohesin binding sites differ between the two tissues and these show reduced overlap with CCCTC-binding factor (CTCF) and are enriched at the regulatory regions of tissue-specific genes. Cohesin/CTCF sites at active enhancers and promoters contain, at least, cohesin-SA1. Analyses of chromatin contacts at the Protocadherin (Pcdh) and Regenerating islet-derived (Reg) gene clusters, mostly expressed in brain and pancreas, respectively, revealed remarkable differences that correlate with the presence of cohesin. We could not detect significant changes in the chromatin contacts at the Pcdh locus when comparing brains from wild-type and SA1 null embryos. In contrast, reduced dosage of SA1 altered the architecture of the Reg locus and decreased the expression of Reg genes in the pancreas of SA1 heterozygous mice. Given the role of Reg proteins in inflammation, such reduction may contribute to the increased incidence of pancreatic cancer observed in these animals.

Transfemoral implantation of Edwards Sapien XT aortic valve without previous valvuloplasty: role of 2D/3D transesophageal echocardiography.

BACKGROUND: Balloon valvuloplasty (BAV) has been considered a mandatory step before TAVI. However, it might be related to cerebrovascular microembolizations, atrioventricular conduction disturbances, and hemodynamic instability. The aim of this study is to describe transesophageal echocardiography characteristics of patients that could benefit from direct transfemoral transcatheter aortic valve implantation (TAVI) of Edwards SAPIEN XT, without previous BAV. METHODS AND RESULTS: A total of 16 patients with direct implantation of an Edwards SAPIEN XT valve are included. Preprocedural echocardiographic findings were exhaustively analyzed and described. From 32 patients elected for transfemoral TAVI with an Edwards SAPIEN XT, 16 of them (50%) were selected for direct implantation using the Edwards SAPIEN XT valve of size 23 mm (n = 5), 26 mm (n = 8), or 29 mm (n = 3). Patients selection for direct TAVI presented three echocardiographic conditions: central effective orifice, moderate to severe calcification of the aortic valve apparatus preserving leaflets movement, and symmetric distribution of calcium with absent to moderate central aortic regurgitation. Mean age was 81.4 ± 7.4, 75% female, with a mean logistic Euroscore 18.2 ± 11.2. Preprocedural mean valve gradient was 43.6 ± 16.3. Mean effective orifice area was 0.7 ± 0.2. There was no valve embolization and the success rate was 100%. Postdilation was performed in one patient (6.25%). New permanent pacing was needed in two patients (12.5%). CONCLUSIONS: TAVI without previous BAV is feasible and safe. 2D/3D TEE is an essential tool to select the patients that could benefit from this technique.

Reconstruction of novel cyanobacterial siphovirus genomes from Mediterranean metagenomic fosmids.

Cellular metagenomes are primarily used for investigating microbial community structure and function. However, cloned fosmids from such metagenomes capture phage genome fragments that can be used as a source of phage genomes. We show that fosmid cloning from cellular metagenomes and sequencing at a high coverage is a credible alternative to constructing metaviriomes and allows capturing and assembling novel, complete phage genomes. It is likely that phages recovered from cellular metagenomes are those replicating within cells during sample collection and represent "active" phages, naturally amplifying their genomic DNA and increasing chances for cloning. We describe five sets of siphoviral contigs (MEDS1, MEDS2, MEDS3, MEDS4, and MEDS5), obtained by sequencing fosmids from the cellular metagenome of the deep chlorophyll maximum in the Mediterranean. Three of these represent complete siphoviral genomes and two represent partial ones. This is the first set of phage genomes assembled directly from cellular metagenomic fosmid libraries. They exhibit low sequence similarities to one another and to known siphoviruses but are remarkably similar in overall genome architecture. We present evidence suggesting they infect picocyanobacteria, likely Synechococcus. Four of these sets also define a novel branch in the phylogenetic tree of phage large subunit terminases. Moreover, some of these siphoviral groups are globally distributed and abundant in the oceans, comparable to some known myoviruses and podoviruses. This suggests that, as more siphoviral genomes become available, we will be better able to assess the abundance and influence of this diverse and polyphyletic group in the marine habitat.

The specific contributions of cohesin-SA1 to cohesion and gene expression: implications for cancer and development.

Besides its well-established role in sister chromatid cohesion, cohesin has recently emerged as major player in the organization of interphase chromatin. Such important function is related to its ability to entrap two DNA segments also in cis, thereby facilitating long-range DNA looping which is crucial for transcriptional regulation, organization of replication factories and V(D)J recombination. Vertebrate somatic cells have two different versions of cohesin, containing Smc1, Smc3, Rad21/Scc1 and either SA1 or SA2, but their functional specificity has been largely ignored. We recently generated a knockout mouse model for the gene encoding SA1, and found that this protein is essential to complete embryonic development. Cohesin-SA1 mediates cohesion at telomeres, which is required for their replication. Telomere defects in SA1- deficient cells provoke chromosome segregation errors resulting in aneuploidy despite robust centromere cohesion. This aneuploidy could explain why heterozygous animals have an earlier onset of tumorigenesis. In addition, the genome-wide distribution of cohesin changes dramatically in the absence of SA1, and the complex shows reduced accumulation at promoters and CTCF sites. As a consequence, gene expression is altered, leading to downregulation of biological processes related to a developmental disorder linked to cohesin function, the Cornelia de Lange Syndrome (CdLS). These results point out a prominent role of cohesin-SA1 in transcriptional regulation, with clear implications in the etiology of CdLS.

Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres.

Cohesin is a protein complex originally identified for its role in sister chromatid cohesion, although increasing evidence portrays it also as a major organizer of interphase chromatin. Vertebrate cohesin consists of Smc1, Smc3, Rad21/Scc1 and either stromal antigen 1 (SA1) or SA2. To explore the functional specificity of these two versions of cohesin and their relevance for embryonic development and cancer, we generated a mouse model deficient for SA1. Complete ablation of SA1 results in embryonic lethality, while heterozygous animals have shorter lifespan and earlier onset of tumourigenesis. SA1-null mouse embryonic fibroblasts show decreased proliferation and increased aneuploidy as a result of chromosome segregation defects. These defects are not caused by impaired centromeric cohesion, which depends on cohesin-SA2. Instead, they arise from defective telomere replication, which requires cohesion mediated specifically by cohesin-SA1. We propose a novel mechanism for aneuploidy generation that involves impaired telomere replication upon loss of cohesin-SA1, with clear implications in tumourigenesis.

A unique role of cohesin-SA1 in gene regulation and development.

Vertebrates have two cohesin complexes that consist of Smc1, Smc3, Rad21/Scc1 and either SA1 or SA2, but their functional specificity is unclear. Mouse embryos lacking SA1 show developmental delay and die before birth. Comparison of the genome-wide distribution of cohesin in wild-type and SA1-null cells reveals that SA1 is largely responsible for cohesin accumulation at promoters and at sites bound by the insulator protein CTCF. As a consequence, ablation of SA1 alters transcription of genes involved in biological processes related to Cornelia de Lange syndrome (CdLS), a genetic disorder linked to dysfunction of cohesin. We show that the presence of cohesin-SA1 at the promoter of myc and of protocadherin genes positively regulates their expression, a task that cannot be assumed by cohesin-SA2. Lack of SA1 also alters cohesin-binding pattern along some gene clusters and leads to dysregulation of genes within. We hypothesize that impaired cohesin-SA1 function in gene expression underlies the molecular aetiology of CdLS.

Expression and functional validation of new p38α transcriptional targets in tumorigenesis.

p38α MAPK (mitogen-activated protein kinase) plays an important tumour suppressor role, which is mediated by both its negative effect on cell proliferation and its pro-apoptotic activity. Surprisingly, most tumour suppressor mechanisms co-ordinated by p38α have been reported to occur at the post-translational level. This contrasts with the important role of p38α in the regulation of transcription and the profound changes in gene expression that normally occur during tumorigenesis. We have analysed whole-genome expression profiles of Ras-transformed wild-type and p38α-deficient cells and have identified 202 genes that are potentially regulated by p38α in transformed cells. Expression analysis has confirmed the regulation of these genes by p38α in tumours, and functional validation has identified several of them as probable mediators of the tumour suppressor effect of p38α on Ras-induced transformation. Interestingly, approx. 10% of the genes that are negatively regulated by p38α in transformed cells contribute to EGF (epidermal growth factor) receptor signalling. Our results suggest that inhibition of EGF receptor signalling by transcriptional targets of p38α is an important function of this signalling pathway in the context of tumour suppression.

MSK2 inhibits p53 activity in the absence of stress.

Mitogen- and stress-activated kinase 2 (MSK2) inhibits the transcription factor p53, and we investigate here the mechanisms underlying this inhibition. In the absence of stress stimuli, MSK2 selectively suppressed the expression of a subset of p53 target genes. This basal inhibition of p53 by MSK2 occurred independently of its kinase activity and of upstream mitogen-activated protein kinase signaling to MSK2. Furthermore, MSK2 interacted with and inhibited the p53 coactivator p300 and associated with the Noxa promoter. Apoptotic stimuli promoted the degradation of MSK2, thus relieving its inhibition of p53 and enabling efficient p53-dependent transactivation of Noxa, which contributed to apoptosis. Together, these findings constitute a new mechanism for the regulation of p53 transcriptional activity in response to stress.

p38 Mitogen-activated protein kinase- and HuR-dependent stabilization of p21(Cip1) mRNA mediates the G(1)/S checkpoint.

Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the G(2)/M cell cycle arrest induced by DNA damage, but little is known about the role of this signaling pathway in the G(1)/S transition. Upregulation of the cyclin-dependent kinase inhibitor p21(Cip1) is thought to make a major contribution to the G(1)/S cell cycle arrest induced by gamma radiation. We show here that inhibition of p38 MAPK impairs p21(Cip1) accumulation and, as a result, the ability of cells to arrest in G(1) in response to gamma radiation. We found that p38 MAPK induces p21(Cip1) mRNA stabilization, without affecting its transcription or the stability of the protein. In particular, p38 MAPK phosphorylates the mRNA binding protein HuR on Thr118, which results in cytoplasmic accumulation of HuR and its enhanced binding to the p21(Cip1) mRNA. Our findings help to understand the emerging role of p38 MAPK in the cellular responses to DNA damage and reveal the existence of p53-independent networks that cooperate in modulating p21(Cip1) levels at the G(1)/S checkpoint.

New insights into RSK activation and hematopoietic cancer.

The tyrosine kinase receptor FGFR3 is thought to play a role in hematopoietic malignancies. A new study in this issue of Cancer Cell identifies the serine/threonine kinase RSK2 as a key substrate of FGFR3 in human t(4;14)-positive multiple myeloma (MM) cells. Constitutively active FGFR3 directly phosphorylates RSK2 on Tyr529, which primes RSK2 for activation by the kinases ERK1 and ERK2 (ERK1/2). In turn, RSK2 activity plays an important role in the survival of FGFR3-expressing MM cells.

p18(Hamlet) mediates different p53-dependent responses to DNA-damage inducing agents.

Cells organize appropriate responses to environmental cues by activating specific signaling networks. Two proteins that play key roles in coordinating stress responses are the kinase p38alpha (MAPK14) and the transcription factor p53 (TP53). Depending on the nature and the extent of the stress-induced damage, cells may respond by arresting the cell cycle or by undergoing cell death, and these responses are usually associated with the phosphorylation of particular substrates by p38alpha as well as the activation of specific target genes by p53. We recently characterized a new p38alpha substrate, named p18(Hamlet) (ZNHIT1), which mediates p53-dependent responses to different genotoxic stresses. Thus, cisplatin or UV light induce stabilization of the p18(Hamlet) protein, which then enhances the ability of p53 to bind to and activate the promoters of pro-apoptotic genes such as NOXA and PUMA leading to apoptosis induction. In a similar way, we report here that p18(Hamlet) can also mediate the cell cycle arrest induced in response to gamma-irradiation, by participating in the p53-dependent upregulation of the cell cycle inhibitor p21(Cip1) (CDKN1A).