63 research outputs found
c-MYC oncoprotein dictates transcriptional profiles of ATP-binding cassette transporter genes in Chronic Myelogenous Leukemia CD34+ hematopoietic progenitor cells
No full textResistance to chemotherapeutic agents remains one of the major impediments to a successful treatment of chronic myeloid leukemia (CML). Misregulation of the activity of a specific group of
ATP-binding cassette transporters (ABC) is responsible for reducing the intracellular concentration of drugs in leukemic cells. Moreover, a consistent body of evidence also suggests that ABC
transporters play a role in cancer progression beyond the efflux of cytotoxic drugs. Despite a large number of studies that investigated the function of the ABC transporters, little is known about the transcriptional regulation of the ABC genes. Here, we present data showing that the oncoprotein c-MYC is a direct transcriptional regulator of a large set of ABC transporters in CML. Furthermore, molecular analysis carried out in CD34+ hematopoietic cell precursors of 21 CML patients reveals
that the overexpression of ABC transporters driven by c-MYC is a peculiar characteristic of the CD34+ population in CML and was not found either in the population of mononuclear cells from
which they had been purified nor in CD34+ cells isolated from healthy donors. Finally, we describe how the methylation state of CpG islands may regulate the access of c-MYC to ABCG2 gene
promoter, a well-studied gene associated with multidrug resistance in CML, hence affecting its expression. Taken together, our findings support a model in which c-MYC-driven transcriptional
events, combined with epigenetic mechanisms, direct and regulate the expression of ABC genes, with possible implications in tumor malignancy and drug efflux in CML
Amélioration des performances de la coloscopie : quels sont les outils réellement utiles?
No full textTurning telomeres off and on
No full textWe envision multiple steps in telomere maintenance, based largely on genetic data from budding yeast. First, the telomere must unfold or open itself such that the free end is accessible to the appropriate enzymatic machinery. Second, telomerase must be recruited, together with the DNA replication machinery that synthesizes the C-rich strand. The processivity of telomerase is regulated both by a length-sensing feedback mechanism and by second-strand synthesis. Finally, the telosome refolds into a protective end structure. If telomerase is nonfunctional, recombination may occur once telomeres are open. Multiple pathways regulate these different steps, producing a highly dynamic chromosomal cap
Regulating repression: roles for the sir4 N-terminus in linker DNA protection and stabilization of epigenetic states.
No full textSilent information regulator proteins Sir2, Sir3, and Sir4 form a heterotrimeric complex that represses transcription at subtelomeric regions and homothallic mating type (HM) loci in budding yeast. We have performed a detailed biochemical and genetic analysis of the largest Sir protein, Sir4. The N-terminal half of Sir4 is dispensable for SIR-mediated repression of HM loci in vivo, except in strains that lack Yku70 or have weak silencer elements. For HM silencing in these cells, the C-terminal domain (Sir4C, residues 747-1,358) must be complemented with an N-terminal domain (Sir4N; residues 1-270), expressed either independently or as a fusion with Sir4C. Nonetheless, recombinant Sir4C can form a complex with Sir2 and Sir3 in vitro, is catalytically active, and has sedimentation properties similar to a full-length Sir4-containing SIR complex. Sir4C-containing SIR complexes bind nucleosomal arrays and protect linker DNA from nucleolytic digestion, but less effectively than wild-type SIR complexes. Consistently, full-length Sir4 is required for the complete repression of subtelomeric genes. Supporting the notion that the Sir4 N-terminus is a regulatory domain, we find it extensively phosphorylated on cyclin-dependent kinase consensus sites, some being hyperphosphorylated during mitosis. Mutation of two major phosphoacceptor sites (S63 and S84) derepresses natural subtelomeric genes when combined with a serendipitous mutation (P2A), which alone can enhance the stability of either the repressed or active state. The triple mutation confers resistance to rapamycin-induced stress and a loss of subtelomeric repression. We conclude that the Sir4 N-terminus plays two roles in SIR-mediated silencing: it contributes to epigenetic repression by stabilizing the SIR-mediated protection of linker DNA; and, as a target of phosphorylation, it can destabilize silencing in a regulated manner
Small-bowel capsule endoscopy in patients with Meckel's diverticulum: clinical features, diagnostic workup, and findings. A European multicenter I-CARE study
No full text(International Capsule Endoscopy Research (I-CARE) Meckel study group).
Background and aims: Meckel's diverticulum (MD) may remain silent or be associated with adverse events such as GI bleeding. The main aim of this study was to evaluate indicative small-bowel capsule endoscopy (SBCE) findings, and the secondary aim was to describe clinical presentation in patients with MD.
Methods: This retrospective European multicenter study included patients with MD undergoing SBCE from 2001 until July 2021.
Results: Sixty-nine patients with a confirmed MD were included. Median age was 32 years with a male-to-female ratio of approximately 3:1. GI bleeding or iron-deficiency anemia was present in nearly all patients. Mean hemoglobin was 7.63 ± 1.8 g/dL with a transfusion requirement of 52.2%. Typical capsule endoscopy (CE) findings were double lumen (n = 49 [71%]), visible entrance into the MD (n = 49 [71%]), mucosal webs (n = 30 [43.5%]), and bulges (n = 19 [27.5%]). Two or more of these findings were seen in 48 patients (69.6%). Ulcers were detected in 52.2% of patients (n = 36). In 63.8% of patients (n = 44), a combination of double lumen and visible entrance into the MD was evident, additionally revealing ulcers in 39.1% (n = 27). Mean percent SB (small bowel) transit time for the first indicative image of MD was 57% of the total SB transit time.
Conclusions: Diagnosis of MD is rare and sometimes challenging, and a preoperative criterion standard does not exist. In SBCE, the most frequent findings were double-lumen sign and visible diverticular entrance, sometimes together with ulcers
Analysis of Sir2p Domains Required for rDNA and Telomeric Silencing in <i>Saccharomyces cerevisiae</i>
No full textSilent information regulator (Sir) 2 is a limiting component of the Sir2/3/4 complex, which represses transcription at subtelomeric and HM loci. Sir2p also acts independently of Sir3p and Sir4p to influence chromatin organization in the rDNA locus. Deleted and mutated forms of Sir2p have been tested for their ability to complement and/or to disrupt silencing. The highly conserved C-terminal domain of Sir2p (aa 199-562) is insufficient to restore repression at either telomeric or rDNA reporters in a sir2Delta background and fails to nucleate silencing when targeted to an appropriate reporter gene. However, its expression in an otherwise wild-type strain disrupts telomeric repression. Similarly, a point mutation (P394L) within this conserved core inactivates the full-length protein but renders it dominant negative for all types of silencing. Deletion of aa 1-198 from Sir2(394L) eliminates its dominant negative effect. Thus we define two distinct functional domains in Sir2p, both essential for telomeric and rDNA repression: the conserved core domain found within aa 199-562 and a second domain that encompasses aa 94-198. Immunolocalization and two-hybrid studies show that aa 94-198 are required for the binding of Sir2p to Sir4p and for the targeting of Sir2p to the nucleolus through another ligand. The globular core domain provides an essential silencing function distinct from that of targeting or Sir complex formation that may reflect its reported mono-ADP-ribosyl transferase activity
Oncogenic c-Myc induces replication stress by increasing cohesins chromatin occupancy in a CTCF-dependent manner.
No full textOncogene-induced replication stress is a crucial driver of genomic instability and one of the key events contributing to the onset and evolution of cancer. Despite its critical role in cancer, the mechanisms that generate oncogene-induced replication stress remain not fully understood. Here, we report that an oncogenic c-Myc-dependent increase in cohesins on DNA contributes to the induction of replication stress. Accumulation of cohesins on chromatin is not sufficient to cause replication stress, but also requires cohesins to accumulate at specific sites in a CTCF-dependent manner. We propose that the increased accumulation of cohesins at CTCF site interferes with the progression of replication forks, contributing to oncogene-induced replication stress. This is different from, and independent of, previously suggested mechanisms of oncogene-induced replication stress. This, together with the reported protective role of cohesins in preventing replication stress-induced DNA damage, supports a double-edge involvement of cohesins in causing and tolerating oncogene-induced replication stress
Oncogenic c-Myc induces replication stress by increasing cohesins chromatin occupancy in a CTCF-dependent manner
No full textOncogene-induced replication stress is a crucial driver of genomic instability and one of the key events contributing to the onset and evolution of cancer. Despite its critical role in cancer, the mechanisms that generate oncogene-induced replication stress remain not fully understood. Here, we report that an oncogenic c-Myc-dependent increase in cohesins on DNA contributes to the induction of replication stress. Accumulation of cohesins on chromatin is not sufficient to cause replication stress, but also requires cohesins to accumulate at specific sites in a CTCF-dependent manner. We propose that the increased accumulation of cohesins at CTCF site interferes with the progression of replication forks, contributing to oncogene-induced replication stress. This is different from, and independent of, previously suggested mechanisms of oncogene-induced replication stress. This, together with the reported protective role of cohesins in preventing replication stress-induced DNA damage, supports a double-edge involvement of cohesins in causing and tolerating oncogene-induced replication stress
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