PML–RARA-RXR Oligomers Mediate Retinoid and Rexinoid/cAMP Cross-Talk in Acute Promyelocytic Leukemia Cell Differentiation

PML–RARA was proposed to initiate acute promyelocytic leukemia (APL) through PML–RARA homodimer–triggered repression. Here, we examined the nature of the PML–RARA protein complex and of its DNA targets in APL cells. Using a selection/amplification approach, we demonstrate that PML–RARA targets consist of two AGGTCA elements in an astonishing variety of orientations and spacings, pointing to highly relaxed structural constrains for DNA binding and identifying a major gain of function of this oncogene. PML–RARA-specific response elements were identified, which all conveyed a major transcriptional response to RA only in APL cells. In these cells, we demonstrate that PML–RARA oligomers are complexed to RXR. Directly probing PML–RARA function in APL cells, we found that the differentiation enhancer cyclic AMP (cAMP) boosted transcriptional activation by RA. cAMP also reversed the normal silencing (subordination) of the transactivating function of RXR when bound to RARA or PML–RARA, demonstrating that the alternate rexinoid/cAMP-triggered APL differentiation pathway also activates PML–RARA targets. Finally, cAMP restored both RA-triggered differentiation and PML–RARA transcriptional activation in mutant RA-resistant APL cells. Collectively, our findings directly demonstrate that APL cell differentiation parallels transcriptional activation through PML–RARA-RXR oligomers and that those are functionally targeted by cAMP, identifying this agent as another oncogene-targeted therapy

A coordinated phosphorylation cascade initiated by MSK1 directs RAR alpha recruitment to target gene promoters

The nuclear retinoic acid (RA) receptor alpha (RARα) is a transcriptional transregulator that controls the expression of specific gene subsets through binding at response elements and dynamic interactions with coregulators, which are coordinated by the ligand. Here, we highlighted a novel paradigm in which the transcription of RARα-target genes is controlled by phosphorylation cascades initiated by the rapid RA activation of the p38MAPK/MSK1 pathway. We demonstrate that MSK1 phosphorylates RARα at S369 located in the Ligand Binding Domain, allowing the binding of TFIIH and thereby phosphorylation of the N-terminal domain at S77 by cdk7/cyclin H. MSK1 also phosphorylates Histone H3 at S10. Finally, the phosphorylation cascade initiated by MSK1 is required for the recruitment of RARα/TFIIH complexes to response elements and subsequently for RARα target genes activation. Cancer cells characterized by a deregulated p38MAPK/MSK1 pathway, do not respond to RA, outlining the essential contribution of the RA-triggered phosphorylation cascade in RA signaling

Effects of high doses of selenium, as sodium selenite, in septic shock: a placebo-controlled, randomized, double-blind, phase II study

INTRODUCTION: Sepsis is associated with the generation of oxygen free radicals and (lacking) decreased selenium plasma concentrations. High doses of sodium selenite might reduce inflammation by a direct pro-oxidative effect and may increase antioxidant cell capacities by selenium incorporation into selenoenzymes. We investigated the effects of a continuous administration of high doses of selenium in septic shock patients. METHODS: A prospective, multicentre, placebo-controlled, randomized, double-blind study was performed with an intention-to-treat analysis in severe septic shock patients with documented infection. Patients received, for 10 days, selenium as sodium selenite (4,000 μg on the first day, 1,000 μg/day on the nine following days) or matching placebo using continuous intravenous infusion. The primary endpoint was the time to vasopressor therapy withdrawal. The duration of mechanical ventilation, the mortality rates in the intensive care unit, at hospital discharge, and at 7, 14, 28 and 180 days and 1 year after randomization, and adverse events were recorded. RESULTS: Sixty patients were included (placebo, n = 29; selenium, n = 31). The median time to vasopressor therapy withdrawal was 7 days in both groups (95% confidence interval = 5–8 and 6–9 in the placebo and selenium groups, respectively; log-rank, P = 0.713). The median duration of mechanical ventilation was 14 days and 19 days in the placebo and selenium groups, respectively (P = 0.762). Mortality rates did not significantly differ between groups at any time point. Rates of adverse events were similar in the two groups. CONCLUSION: Continuous infusion of selenium as sodium selenite (4,000 μg on the first day, 1,000 μg/day on the nine following days) had no obvious toxicity but did not improve the clinical outcome in septic shock patients. Trial Registration = NCT00207844

In Vivo Activation of cAMP Signaling Induces Growth Arrest and Differentiation in Acute Promyelocytic Leukemia

Differentiation therapy for acute myeloid leukemia uses transcriptional modulators to reprogram cancer cells. The most relevant clinical example is acute promyelocytic leukemia (APL), which responds dramatically to either retinoic acid (RA) or arsenic trioxide (As2O3). In many myeloid leukemia cell lines, cyclic adenosine monophosphate (cAMP) triggers growth arrest, cell death, or differentiation, often in synergy with RA. Nevertheless, the toxicity of cAMP derivatives and lack of suitable models has hampered trials designed to assess the in vivo relevance of theses observations. We show that, in an APL cell line, cAMP analogs blocked cell growth and unraveled As2O3-triggered differentiation. Similarly, in RA-sensitive or RA-resistant mouse models of APL, continuous infusions of 8-chloro-cyclic adenosine monophosphate (8-Cl-cAMP) triggered major growth arrest, greatly enhanced both spontaneous and RA- or As2O3-induced differentiation and accelerated the restoration of normal hematopoiesis. Theophylline, a well-tolerated phosphodiesterase inhibitor which stabilizes endogenous cAMP, also impaired APL growth and enhanced spontaneous or As2O3-triggered cell differentiation in vivo. Accordingly, in an APL patient resistant to combined RA–As2O3 therapy, theophylline induced blast clearance and restored normal hematopoiesis. Taken together, these results demonstrate that in vivo activation of cAMP signaling contributes to APL clearance, independently of its RA-sensitivity, thus raising hopes that other myeloid leukemias may benefit from this therapeutic approach

Co, conseil & stratégies pour l’intérêt général

Consultant en organisation et stratégie, je suis également depuis cinq ans administrateur de l’association professionnelle des cabinets de conseil : Syntec Conseil en Management. Avec l’association Le RAMEAU j’y anime un groupe de travail qui vise à créer les conditions du développement de l’engagement sociétal des cabinets de conseil. L’étude préalable que nous avons menée a mis en lumière le fait que les grandes associations d’intérêt général d’envergure nationale ont de grandes difficultés..

La représentation de la profession de chirurgien-dentiste dans les oeuvres cinématographiques de fiction (analyse descriptive, psychologique et sociologique)

NANCY1-SCD Pharmacie-Odontologie (543952101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF