The Effect of HMGB1 and HMGB2 on Transcriptional Regulation Differs in Neuroendocrine and Adenocarcinoma Models of Prostate Cancer.

Human high-mobility group-B (HMGB) proteins regulate gene expression in prostate cancer (PCa), a leading cause of oncological death in men. Their role in aggressive PCa cancers, which do not respond to hormonal treatment, was analyzed. The effects of and silencing upon the expression of genes previously related to PCa were studied in the PCa cell line PC-3 (selected as a small cell neuroendocrine carcinoma, SCNC, PCa model not responding to hormonal treatment).

Thanksgiving to Yeast, the HMGB Proteins History from Yeast to Cancer.

Yeasts have been a part of human life since ancient times in the fermentation of many natural products used for food. In addition, in the 20th century, they became powerful tools to elucidate the functions of eukaryotic cells as soon as the techniques of molecular biology developed. Our molecular understandings of metabolism, cellular transport, DNA repair, gene expression and regulation, and the cell division cycle have all been obtained through biochemistry and genetic analysis using different yeasts.

HMG Proteins from Molecules to Disease.

High Mobility Group (HMG) proteins are today the focus of interest due to their participation in human degenerative diseases and inflammatory responses [...

HMGB1 Protein Interactions in Prostate and Ovary Cancer Models Reveal Links to RNA Processing and Ribosome Biogenesis through NuRD, THOC and Septin Complexes.

This study reports the HMGB1 interactomes in prostate and ovary cancer cells lines. Affinity purification coupled to mass spectrometry confirmed that the HMGB1 nuclear interactome is involved in HMGB1 known functions such as maintenance of chromatin stability and regulation of transcription, and also in not as yet reported processes such as mRNA and rRNA processing. We have identified an interaction between HMGB1 and the NuRD complex and validated this by yeast-two-hybrid, confirming that the RBBP7 subunit directly interacts with HMGB1.

The HMGB Protein Ixr1, a DNA Binding Regulator of Gene Expression Involved in Oxidative Metabolism, Growth, and dNTP Synthesis.

In the traditional fermentative model yeast , Ixr1 is an HMGB (High Mobility Group box B) protein that has been considered as an important regulator of gene transcription in response to external changes like oxygen, carbon source, or nutrient availability. is also a useful eukaryotic model, more similar to many human cells due to its respiratory metabolism. We cloned and functionally characterized by different methodologies IXR1, which encodes a protein with only 34.

The HMGB1-2 Ovarian Cancer Interactome. The Role of HMGB Proteins and Their Interacting Partners MIEN1 and NOP53 in Ovary Cancer and Drug-Response.

High mobility group box B (HMGB) proteins are overexpressed in different types of cancers such as epithelial ovarian cancers (EOC). We have determined the first interactome of HMGB1 and HMGB2 in epithelial ovarian cancer (the EOC-HMGB interactome). Libraries from the SKOV-3 cell line and a primary transitional cell carcinoma (TCC) ovarian tumor were tested by the Yeast Two Hybrid (Y2H) approach.

The Challenges and Opportunities of LncRNAs in Ovarian Cancer Research and Clinical Use.

Ovarian cancer is one of the most lethal gynecological malignancies worldwide because it tends to be detected late, when the disease has already spread, and prognosis is poor. In this review we aim to highlight the importance of long non-coding RNAs (lncRNAs) in diagnosis, prognosis and treatment choice, to make progress towards increasingly personalized medicine in this malignancy. We review the effects of lncRNAs associated with ovarian cancer in the context of cancer hallmarks.

Characterization of HMGB1/2 Interactome in Prostate Cancer by Yeast Two Hybrid Approach: Potential Pathobiological Implications.

High mobility group box B (HMGB) proteins are pivotal in the development of cancer. Although the proteomics of prostate cancer (PCa) cells has been reported, the involvement of HMGB proteins and their interactome in PCa is an unexplored field of considerable interest. We describe herein the results of the first HMGB1/HMGB2 interactome approach to PCa.

Differential Characteristics of HMGB2 Versus HMGB1 and their Perspectives in Ovary and Prostate Cancer.

We have summarized common and differential functions of HMGB1 and HMGB2 proteins with reference to pathological processes, with a special focus on cancer. Currently, several "omic" approaches help us compare the relative expression of these 2 proteins in healthy and cancerous human specimens, as well as in a wide range of cancer-derived cell lines, or in fetal versus adult cells. Molecules that interfere with HMGB1 functions, though through different mechanisms, have been extensively tested as therapeutic agents in animal models in recent years, and their effects are summarized.

Delineating the HMGB1 and HMGB2 interactome in prostate and ovary epithelial cells and its relationship with cancer.

High Mobility Group B (HMGB) proteins are involved in cancer progression and in cellular responses to platinum compounds used in the chemotherapy of prostate and ovary cancer. Here we use affinity purification coupled to mass spectrometry (MS) and yeast two-hybrid (Y2H) screening to carry out an exhaustive study of HMGB1 and HMGB2 protein interactions in the context of prostate and ovary epithelia. We present a proteomic study of HMGB1 partners based on immunoprecipitation of HMGB1 from a non-cancerous prostate epithelial cell line.

Ixr1 Regulates Ribosomal Gene Transcription and Yeast Response to Cisplatin.

Ixr1 is a Saccharomyces cerevisiae HMGB protein that regulates the hypoxic regulon and also controls the expression of other genes involved in the oxidative stress response or re-adaptation of catabolic and anabolic fluxes when oxygen is limiting. Ixr1 also binds with high affinity to cisplatin-DNA adducts and modulates DNA repair. The influence of Ixr1 on transcription in the absence or presence of cisplatin has been analyzed in this work.

The HMGB protein Ixr1 interacts with Ssn8 and Tdh3 involved in transcriptional regulation.

Ixr1 is a Saccharomyces cerevisiae transcriptional factor that extensively regulates the response to hypoxia and controls other important cellular functions and DNA repair. During aerobic growth, the Ixr1 repressor function is predominant on regulated promoters of hypoxic genes, although activator effects are also observed on other genes. During hypoxia, Ixr1 expression increases and the number of genes activated by Ixr1 also increase.

Transcriptome analysis of the thermotolerant yeast Kluyveromyces marxianus CCT 7735 under ethanol stress.

The thermotolerant yeast Kluyveromyces marxianus displays a potential to be used for ethanol production from both whey and lignocellulosic biomass at elevated temperatures, which is highly alluring to reduce the cost of the bioprocess. Nevertheless, contrary to Saccharomyces cerevisiae, K. marxianus cannot tolerate high ethanol concentrations.

Promoter-Terminator Gene Loops Affect Alternative 3'-End Processing in Yeast.

Many eukaryotic genes undergo alternative 3'-end poly(A)-site selection producing transcript isoforms with 3'-UTRs of different lengths and post-transcriptional fates. Gene loops are dynamic structures that juxtapose the 3'-ends of genes with their promoters. Several functions have been attributed to looping, including memory of recent transcriptional activity and polarity of transcription initiation.

High Mobility Group B Proteins, Their Partners, and Other Redox Sensors in Ovarian and Prostate Cancer.

Cancer cells try to avoid the overproduction of reactive oxygen species by metabolic rearrangements. These cells also develop specific strategies to increase ROS resistance and to express the enzymatic activities necessary for ROS detoxification. Oxidative stress produces DNA damage and also induces responses, which could help the cell to restore the initial equilibrium.

KlGcr1 controls glucose-6-phosphate dehydrogenase activity and responses to H2O2, cadmium and arsenate in Kluyveromyces lactis.

It has been previously reported that Gcr1 differentially controls growth and sugar utilization in Saccharomyces cerevisiae and Kluyveromyces lactis, although the regulatory mechanisms causing activation of glycolytic genes are conserved (Neil et al., 2004). We have found that KlGCR1 deletion diminishes glucose consumption and ethanol production, but increases resistance to oxidative stress caused by H2O2, cadmium and arsenate, glucose 6P dehydrogenase activity, and the NADPH/NADP(+) and GSH/GSSG ratios in K.

Structurally conserved and functionally divergent yeast Ssu72 phosphatases.

The eukaryotic Ssu72 factor is involved in several RNA biogenesis processes. It has phosphatase activity on the carboxy-terminal domain (CTD) of the major subunit of RNA polymerase II. The Kluyveromyces lactis Ssu72 (KlSsu72) shows in vitro phosphatase activity for the pNPP substrate, and this activity is inhibited by ortho-vanadate.

The yeast hypoxic responses, resources for new biotechnological opportunities.

Recent advances in the knowledge of molecular mechanisms that control the adaptation to low oxygen levels in yeast and their biotechnological applications, including bioproduct synthesis, such as ethanol, glutathione or recombinant proteins, as well as pathogenic virulence, are reviewed. Possible pathways and target genes, which might be of particular interest for the improvement of biotechnological applications, are evaluated.

KlRox1p contributes to yeast resistance to metals and is necessary for KlYCF1 expression in the presence of cadmium.

We have characterized the KlROX1 gene from Kluyveromyces lactis and verified that it does not regulate the hypoxic response in this yeast, oppositely to the Saccharomyces cerevisiae homologue ScROX1. The KlROX1 promoter is not regulated by KlHap1p or KlRox1p in response to changes aerobiosis/hypoxia. Besides, KlRox1p expression only partially represses ScANB1 in S.

Ixr1p and the control of the Saccharomyces cerevisiae hypoxic response.

In Saccharomyces cerevisiae, adaptation to hypoxia/anaerobiosis requires the transcriptional induction or derepression of multiple genes organized in regulons controlled by specific transcriptional regulators. Ixr1p is a transcriptional regulatory factor that causes aerobic repression of several hypoxic genes (COX5B, TIR1, and HEM13) and also the activation of HEM13 during hypoxic growth. Analysis of the transcriptome of the wild-type strain BY4741 and its isogenic derivative Δixr1, grown in aerobic and hypoxic conditions, reveals differential regulation of genes related not only to the hypoxic and oxidative stress responses but also to the re-adaptation of catabolic and anabolic fluxes in response to oxygen limitation.

A stress response related to the carbon source and the absence of KlHAP2 in Kluyveromyces lactis.

The Kluyveromyces lactis HIS4 gene (KlHIS4) is transcriptionally regulated by the carbon source. The promoter region encompassing positions -238 to -139 is responsible for this regulation according to lacZ reporter assays. Electrophoretic Mobility Shift Assay (EMSA) experiments on KlHIS4 promoter (positions -218 to -213, Fragment 6, F6) show a specific gel-shift band, CS1, whose intensity is carbon-source dependent in K.

Transcriptional repression by Kluyveromyces lactis Tup1 in Saccharomyces cerevisiae.

The general repression complex, constituted by the yeast Tup1 and Ssn6 factors, is a conserved global regulator of transcription in eukaryotes. In the yeast Saccharomyces cerevisiae, it is an important repressor of hypoxic genes, such as ANB1, under aerobic conditions and deletion of the TUP1 gene causes a flocculation phenotype. The KlTUP1 gene from the yeast Kluyveromyces lactis encodes for a protein with 83% similarity to Tup1 in S.

Ixr1p regulates oxygen-dependent HEM13 transcription.

In Saccharomyces cerevisiae, HEM13 encodes the enzyme coproporphyrinogen III oxidase, which catalyzes the rate-limiting step in heme biosynthesis. HEM13 is a regulated hypoxic gene repressed by Rox1p and Mot3p under aerobic conditions. In this study, we further investigate the hypoxic expression of HEM13, focusing on the promoter regions that are functionally important during hypoxia and on the effect of deleting the transcriptional regulators Sut1p, Sut2p, Upc2p, Ecm22p and Ixr1p.