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PML/TRIM19 is the organizer of PML nuclear bodies (NB), large multiprotein structures associated to the nuclear matrix, which recruit a great number of proteins and which are implicated in various cellular processes including antiviral defense. The conjugation of PML to SUMO is required for the formation and function of PML NB. Alternative splicing from a single PML gene generates several PML isoforms (PMLI to PMLVIIb), each harboring a specific carboxy-terminal region. This variability allows each isoform to recruit different partners and thus confers them specific functions. PML gene is directly induced by interferon and certain PML isoforms are implicated in its antiviral properties, as they display intrinsic antiviral activities against RNA or DNA viruses. One isoform, PMLIV, is also implicated in innate immunity by enhancing IFN-β production during a viral infection. Here we review recent findings on PML/TRIM19 implication in interferon response and antiviral defense, at the interface between intrinsic and innate immunity., (© 2014 médecine/sciences – Inserm.)

O-GlcNAcylation corresponds to the addition of N-acetyl glucosamine (GlcNAc) on serine or threonine residues of cytosolic and nuclear proteins. This reversible post-translational modification regulates protein phosphorylation, sub-cellular localisation, stability and activity. Only two enzymes, OGT (O-linked N-acetyl-glucosaminyltransferase) and OGA (O-linked N-acetyl-β-D glucosaminidase), control the addition and removal of GlcNAc from more than a thousand of proteins. Alternative splicing generates different isoforms of OGT and OGA, and address these enzymes to different sub-cellular compartments (mitochondria, cytosol...), restraining their action to specific subsets of substrates. Moreover, interaction with adaptor proteins may also help address these enzymes to specific substrates. Alterations in protein O-GlcNAcylation have been observed in a number of important human diseases, such as Alzheimer, cancer and diabetes. A reciprocal relationship between Tau protein phosphorylation and O-GlcNAcylation has been observed, and decreased O-GlcNAcylation in the brain of patients with Alzheimer diseases may favour Tau aggregation, destabilisation of microtubules and neuronal alterations. Alterations in OGT/OGA expression levels, and in protein O-GlcNAcylation, have been described in different types of cancer, and much evidence indicates that O-GlcNAcylation may participate in abnormal proliferation and migration of cancer cells. O-GlcNAcylation of transcription factors and signalling effectors may also participate in defects observed in diabetes. Indeed, in situation of chronic hyperglycaemia, abnormal O-GlcNAcylation may have deleterious effect on insulin secretion and action, resulting in further impairment of glucose homeostasis. Therefore, O-GlcNAcylation appears to be a major regulator of cellular activities and may play an important part in different human diseases. However, because of the large spectrum of OGT and OGA substrates, targeting O-GlcNAc for treatment of these diseases will be a highly challenging task., (© Société de Biologie, 2014.)

Vitamin B6 is well-known for its role as a cofactor in many enzymatic reactions and recently, several epidemiological studies have highlighted the importance of this vitamin as a protective agent against various cancers: elevated vitamin B6 plasma levels were associated with a lower risk of colorectal cancer development, for example. In vivo studies have shown that vitamin B6 decreased cell proliferation and enhanced the immune response. At the cellular level, antioxidant, pro-apoptotic and anti-angiogenic effects have been identified. At the molecular level, vitamin B6 is able to inhibit the transactivation potential of various nuclear receptors. Interestingly, a recent paper has described the conjugation of vitamin B6 to RIP140 (receptor interacting protein of 140 kDa), a protein that acts as a transcriptional corepressor of nuclear receptors. This post-translational modification increases the transcriptional repression of RIP140 and regulates its subcellular localization and its ability to interact with different protein partners. Finally, vitamin B6 is involved in the methyl donor cycle ant thus, some of the antitumor properties of vitamin B6 may involve an indirect effect on the level of DNA or histone methylation. All of these mechanistic and clinical data justify further studies to decipher the mechanism of action of vitamin B6 and its clinical interest in combination with molecules typically used in chemotherapy or hormonal therapy.

Background: The p73 gene encodes a nuclear protein that is highy homologous to p53. p73 also shares some common functions with p53 protein indicating that p73 gene is a p53-like tumor suppressor., Aim: In this study, we examined by immunohistochemestry the p73 expression on 120 cases of colorectal carcinomas and evaluated its implication in carcinogenesis., Methods: Retrospective study., Results: The results show an increase of intensity and distribution of p73 in common adenocarcinoma from the normal mucosa, to primery tumors and to metastases. However, in mucinous adenocarcinomas, immunostaining of p73 decrease in primary tumor and completely diseappears in isolated cells and metastases compared with matched normal mucosa. These observations are further reinforced by the fact that in adenocarcinoma with mucinous component less than 50%, the positivity of p73 persist in well-differentiated areas and dramatically decreases or completely deseappears in mucinous areas., Conclusion: In conclusion, p73 would be a prognosic marker for the common adenocarcinomas and an ethiopathogenic factor for the mucinous subtype.

Hutchinson-Gilford Progeria (HGPS), a rare and severe developmental disorder characterized by features recalling premature aging, and Restrictive Dermopathy (RD), a neonatal lethal genodermatosis, have recently been identified as being primary or secondary << Laminopathies >>. These heterogeneous disorders are caused by altered Lamin maturation pathway. In physiological conditions, mature Lamin A is obtained through a series of post-translational processing steps performed on a protein precursor, Prelamin A. The major pathophysiological mechanism involved in Progeria is an aberrant splicing due to a de novo heterozygous point mutation, leading to the accumulation of truncated Lamin A precursor. The same aberrant splicing mechanism was involved in RD, whereas the majority of RD cases are caused by ZMPSTE24/FACE1 inactivation, a key enzyme involved in the Lamin A maturation pathway. In functional terms, all these conditions share the same pathophysiological mechanism, i.e. the intranuclear accumulation of Lamin A precursors, which cannot be fully processed and exert a toxic effect on nuclear homeostasis. In this article, we review the structure and functions of A-type Lamins, focusing namely on HGPS, RD or MAD disorders, in relation to existing animal models and possible future therapeutic approaches.

Aims: To study the immunohistochemical expression of HHV8 in Kaposi's lesions and in other vascular lesions and to determine the utility of this technique in differentiating between Kaposi's disease (KD) and other vascular lesions., Methods: Fixed, paraffin-embedded tissue sections from 25 cases of KD, 9 cases of hemangioma, 2 cases of angiolymphoid hyperplasia with eosinophilia and 9 cases of angiosarcoma were examined immunohistochemically using the monoclonal antibody monoclonal LNA 53 (ABI). Strong, nuclear and granular staining in at least a cell was considered as a positive result., Results: Sixteen cases of KD showed positive staining, whereas all cases of hemangioma, angiolymphoid hyperplasia with eosinophilia and angiosarcoma were negative for this antigen, Conclusion: Immunohistochemical detection of the human herpesvirus-8 latent nuclear antigen-1 is a useful for differentiating between KD and other vascular lesions.

Alternative splicing is a process by which a single stretch of genomic DNA yields several mRNAs encoding different proteins. Once believed to be a marginal phenomenon, alternative splicing now appears to be widespread among higher organisms and to be behind a large repertoire of human diseases. It involves a flexible mechanism for selecting splice sites, based on regulatory sequences recognized by cognate trans-acting protein factors (stimulatory SR proteins, or their antagonists). This RNA-protein interaction provides two types of targets for therapeutic manipulation. Masking regulatory RNA sequences with an antisense strategy is the most obvious, and encouraging results are beginning to accrue. Our lab is currently developing an entirely new approach in which activating proteins are targeted by small chemical molecules. A large screening program has been conducted with the chemical library from the Curie Institute. Several molecules (all indole derivatives) were found to counter the stimulatory effects of individual activating proteins, and have been selected for further development.

Hypoxia-inducible factor-1 is a heterodimer made up of an oxygen-regulated HIF1alpha subunit and a constitutively expressed HIF1beta subunit. Among the 70 target genes of HIF-1 known so far, several are involved in angiogenesis, erythropoiesis, cell proliferation, cell viability, and glucose and iron metabolisms. Intratumoral hypoxia or genetic alterations can lead to HIF-1 alpha over-expression. HIF-1 over-expression has been associated with an increased patient mortality rate in many cancer types. Also, in vitro suppression of hif1alpha gene expression has been shown to be efficient in tumour growth repression. During the past five years, drugs able to indirectly inhibit HIF1 activity have been rationally or empirically developed. Some are currently evaluated in clinical trials, but further work has still to be undertaken to rationally identify new specific inhibitors of HIF1 and to test their efficacy as anticancer therapeutics. This review focuses on HIF1 regulation, HIF1 involvement in tumour promotion, the different HIF-1 inhibitors currently tested and their mechanisms of action.

The oncodevelopmentally regulated alpha-fetoprotein (AFP) gene offers a very good model system to better understand the molecular mechanisms which dictate the specificity of gene expression in liver and control its tight modulation in the course of development and carcinogenesis. Transcription factors of the CCAAT/enhance-binding protein (C/EBP), hepatocyte nuclear factor-1 (HNF-1), and nuclear factor-1 (NF-1) families can bind in vitro to the promoter of the rat AFP gene, which makes the expression of the AFP gene specific to the liver. We have evaluated the influence of some of these factors on the activity of the AFP promoter by transfection of HepG2 hepatoma cells with the appropriate expression vector plus a CAT plasmid under the control of the AFP promoter. A similar plasmid bearing the rat albumin promoter was used as a control. C/EBP alpha, and C/EBP beta acted as transactivators on the AFP promoter, while LIP, a truncated form of C/EBP beta, was a potent negative regulator of the promoter. Interestingly, HNF-1 beta was found to be more potent than HNF-1 alpha in activating the AFP promoter in the HepG2 cells. This effect was highly promoter and cell specific since it did not occur with the rat albumin promoter or in Chinese hamster ovary cells. HNF-1 beta, which is produced earlier than HNF-1 alpha during liver development, would thus have the greater influence on the AFP promoter in early development. Our results pointed to a key role that NF1 might play in the functioning of the AFP promoter. Indeed, overexpression of NF1 induced a specific decrease in the activity of the AFP promoter. Competition between NF1 and HNF-1 for binding to their overlapping binding sites on the AFP promoter would be critical for modulating its activity.

During dog-fish spermiogenesis, 2 basic nuclear protein transitions occur: the first from histones to spermatid-specific proteins S1 and S2, the second leading to protamines. S1, the most abundant transition protein, is a polypeptide containing 87 residues (Mr = 11,179 Da) whereas S2, the minor transition protein, contains 80 residues (Mr = 9,726 Da). The 2 proteins are mainly characterized by an asymmetry of the molecule, a very high content of basic residues, a relatively high level of hydrophobic residues and a cluster of acidic residues in the carboxy-terminal quarter of the molecule. The 2 proteins are phosphorylated on serine residues and the degree of phosphorylation is relatively important in protein S1. The 2 transition proteins are structurally unrelated to testis histones or sperm protamines and cannot be considered either as their proteolytic degradation products or as their precursors.