ZNF281/Zfp281 is a target of miR-1 and counteracts muscle differentiation.

Defects in achieving a fully differentiated state and aberrant expression of genes and microRNAs (miRs) involved in differentiation are common to virtually all tumor types. Here, we demonstrate that the zinc finger transcription factor ZNF281/Zfp281 is down-regulated during epithelial, muscle, and granulocytic differentiation in vitro. The expression of this gene is absent in terminally differentiated human tissues, in contrast to the elevated expression in proliferating/differentiating ones.

ZNF281 is recruited on DNA breaks to facilitate DNA repair by non-homologous end joining.

Efficient repair of DNA double-strand breaks (DSBs) is of critical importance for cell survival. Although non-homologous end joining (NHEJ) is the most used DSBs repair pathway in the cells, how NHEJ factors are sequentially recruited to damaged chromatin remains unclear. Here, we identify a novel role for the zinc-finger protein ZNF281 in participating in the ordered recruitment of the NHEJ repair factor XRCC4 at damage sites.

Cell death in cancer in the era of precision medicine.

Tumors constitute a large class of diseases that affect different organs and cell lineages. The molecular characterization of cancers of a given type has revealed an extraordinary heterogeneity in terms of genetic alterations and DNA mutations; heterogeneity that is further highlighted by single-cell DNA sequencing of individual patients. To address these issues, drugs that specifically target genes or altered pathways in cancer cells are continuously developed.

ZNF281 inhibits neuronal differentiation and is a prognostic marker for neuroblastoma.

Derangement of cellular differentiation because of mutation or inappropriate expression of specific genes is a common feature in tumors. Here, we show that the expression of ZNF281, a zinc finger factor involved in several cellular processes, decreases during terminal differentiation of murine cortical neurons and in retinoic acid-induced differentiation of neuroblastoma (NB) cells. The ectopic expression of ZNF281 inhibits the neuronal differentiation of murine cortical neurons and NB cells, whereas its silencing causes the opposite effect.

Is it the time to study air pollution effects under environmental conditions? A case study to support the shift of in vitro toxicology from the bench to the field.

Air pollution and particulate matter are recognised cause of increased disease incidence in exposed population. The toxicological processes underlying air pollution associated effects have been investigated by in vivo and/or in vitro experimentation. The latter is usually performed by exposing cells cultured under submerged condition to particulate matter concentration quite far from environmental exposure expected in humans.

Zinc-finger proteins in health and disease.

Zinc-finger proteins (ZNFs) are one of the most abundant groups of proteins and have a wide range of molecular functions. Given the wide variety of zinc-finger domains, ZNFs are able to interact with DNA, RNA, PAR (poly-ADP-ribose) and other proteins. Thus, ZNFs are involved in the regulation of several cellular processes.

Cytotoxicity, genotoxicity and gene expression changes elicited by exposure of human hepatic cells to Ginkgo biloba leaf extract.

The use of Ginkgo biloba leaf extract as nutraceutical is becoming increasingly common. As a consequence, the definition of a reliable toxicological profile is a priority for its safe utilization. Recently, contrasting data have been reported on the carcinogenic potential of Ginkgo biloba extract in rodent liver.

Multidimensional improvements induced by an intensive obesity inpatients rehabilitation programme.

Purpose: To analyse the short-term effectiveness of an intensive multidimensional inpatient programme specifically developed for patients with severe obesity.

Methods: A multidisciplinary team managed a 3-week residential programme characterised by the integration of nutritional and physical rehabilitation with psychological and educational intervention. All patients consecutively admitted in 10 months were analysed at admission and discharge for changes in the following domains: anthropometry (weight, body mass index (BMI), waist and neck circumferences), cardiovascular risk factors (glycaemia, HbA1c, lipid profile, blood pressure), quality of life, eating behaviour, and physical performance (VO by incremental cycle ergometer test, 6-min walking test (6MWT), chair stands test).

New factors in mammalian DNA repair-the chromatin connection.

In response to DNA damage mammalian cells activate a complex network of stress response pathways collectively termed DNA damage response (DDR). DDR involves a temporary arrest of the cell cycle to allow for the repair of the damage. DDR also attenuates gene expression by silencing global transcription and translation.

DNA repair and aging: the impact of the p53 family.

Cells are constantly exposed to endogenous and exogenous factors that threaten the integrity of their DNA. The maintenance of genome stability is of paramount importance in the prevention of both cancer and aging processes. To deal with DNA damage, cells put into operation a sophisticated and coordinated mechanism, collectively known as DNA damage response (DDR).

Neuroblastoma: oncogenic mechanisms and therapeutic exploitation of necroptosis.

Neuroblastoma (NB) is the most common extracranial childhood tumor classified in five stages (1, 2, 3, 4 and 4S), two of which (3 and 4) identify chemotherapy-resistant, highly aggressive disease. High-risk NB frequently displays MYCN amplification, mutations in ALK and ATRX, and genomic rearrangements in TERT genes. These NB subtypes are also characterized by reduced susceptibility to programmed cell death induced by chemotherapeutic drugs.

ZNF281 contributes to the DNA damage response by controlling the expression of XRCC2 and XRCC4.

ZNF281 is a zinc-finger factor involved in the control of cellular stemness and epithelial-mesenchymal transition (EMT). Here, we report that ZNF281 expression increased after genotoxic stress caused by DNA-damaging drugs. Comet assays demonstrated that DNA repair was delayed in cells silenced for the expression of ZNF281 and treated with etoposide.

Activation of miR200 by c-Myb depends on ZEB1 expression and miR200 promoter methylation.

Tumor progression to metastasis is a complex, sequential process that requires proliferation, resistance to apoptosis, motility and invasion to colonize at distant sites. The acquisition of these features implies a phenotypic plasticity by tumor cells that must adapt to different conditions by modulating several signaling pathways (1) during the journey to the final site of metastasis. Several transcription factors and microRNA play a role in tumor progression, but less is known about the control of their expression during this process.

Inhibiting interactions of lysine demethylase LSD1 with snail/slug blocks cancer cell invasion.

The process of epithelial-mesenchymal transition (EMT) which is required for cancer cell invasion is regulated by a family of E-box-binding transcription repressors, which include Snail (SNAIL1) and Slug (SNAI2). Snail appears to repress the expression of the EMT marker E-cadherin by epigenetic mechanisms dependent on the interaction of its N-terminal SNAG domain with chromatin-modifying proteins including lysine-specific demethylase 1 (LSD1/KDM1A). We assessed whether blocking Snail/Slug-LSD1 interaction by treatment with Parnate, an enzymatic inhibitor of LSD1, or TAT-SNAG, a cell-permeable peptide corresponding to the SNAG domain of Slug, suppresses the motility and invasiveness of cancer cells of different origin and genetic background.

The p53 codon 72 Pro/Pro genotype identifies poor-prognosis neuroblastoma patients: correlation with reduced apoptosis and enhanced senescence by the p53-72P isoform.

The p53 gene is rarely mutated in neuroblastoma, but codon 72 polymorphism that modulates its proapoptotic activity might influence cancer risk and clinical outcome. We investigated whether this polymorphism affects neuroblastoma risk and disease outcome and assessed the biologic effects of the p53-72R and p53-72P isoforms in p53-null cells. Comparison of 288 healthy subjects and 286 neuroblastoma patients revealed that the p53-72 polymorphism had no significant impact on the risk of developing neuroblastoma; however, patients with the Pro/Pro genotype had a shorter survival than those with the Arg/Arg or the Arg/Pro genotypes even in the stage 3 and 4 subgroup without MYCN amplification.

Expression of p89(c-Mybex9b), an alternatively spliced form of c-Myb, is required for proliferation and survival of p210BCR/ABL-expressing cells.

The c-Myb gene encodes the p75(c-Myb) isoform and less-abundant proteins generated by alternatively spliced transcripts. Among these, the best known is p(c-Mybex9b), which contains 121 additional amino acids between exon 9 and 10, in a domain involved in protein-protein interactions and negative regulation. In hematopoietic cells, expression of p(c-Mybex9b) accounts for 10-15% of total c-Myb; these levels may be biologically relevant because modest changes in c-Myb expression affects proliferation and survival of leukemic cells and lineage choice and frequency of normal hematopoietic progenitors.

TGFβ-induced c-Myb affects the expression of EMT-associated genes and promotes invasion of ER+ breast cancer cells.

Advanced breast cancer cells acquire metastatic properties in response to TGFβ. We show here that the expression of c-Myb increases in TGFβ-treated ER (+) breast cancer cells by protein stabilization, transcription activation and release from miR200-dependent down-regulation. In particular, we mapped 2 sites for miR200b, miR200c and miR429 binding in the 3' UTR of the human c-myb gene.

Addiction of MYCN amplified tumours to B-MYB underscores a reciprocal regulatory loop.

MYCN is a member of the MYC family of oncoproteins frequently amplified or overexpressed in aggressive, paediatric tumours of the nervous system. In this study we have identified the gene B-MYB, encoding the transcription factor also known as MYBL2, as a downstream target of MYCN. Using multiple in silico databases we show that expression of B-MYB significantly correlates with that of MYCN in neuroblastoma patients.

Expression of Slug is regulated by c-Myb and is required for invasion and bone marrow homing of cancer cells of different origin.

In metastatic cancer cells, the process of invasion is regulated by several transcription factors that induce changes required for migration and resistance to apoptosis. Slug (SNAI2, Snail2) is involved in epithelial mesenchymal transition in physiological and in pathological contexts. We show here that in embryonic kidney, colon carcinoma, chronic myeloid leukemia-blast crisis, and in neuroblastoma cells, expression of Slug is transcriptionally regulated by c-Myb via Myb binding sites in the 5'-flanking region and in the first intron of the slug gene.

Elongation Factor 1 alpha interacts with phospho-Akt in breast cancer cells and regulates their proliferation, survival and motility.

Background: Akt/PKB is a serine/threonine kinase that has attracted much attention because of its central role in regulating cell proliferation, survival, motility and angiogenesis. Activation of Akt in breast cancer portends aggressive tumour behaviour, resistance to hormone-, chemo-, and radiotherapy-induced apoptosis and it is correlated with decreased overall survival. Recent studies have identified novel tumor-specific substrates of Akt that may provide new diagnostic and prognostic markers and serve as therapeutic targets.

Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model.

Stage 4 neuroblastoma (NB) is a devastating childhood cancer whose poor outcome has remained essentially unchanged in the last 20 years. Receptor tyrosine kinases have important roles in the control of proliferation, differentiation and apoptosis of NB cells. Thus, we tested the activity of second-generation tyrosine kinase inhibitor Dasatinib in human NB cell lines in vitro and in an orthotopic mouse model.