Nuclear retinoic acid (RA) receptors (RARs) activate gene expression through dynamic interactions with coregulators in coordination with the ligand and phosphorylation processes. Here we show that during RA‐dependent activation of the RARα isotype, the p160 coactivator pCIP/ACTR/AIB‐1/RAC‐3/TRAM‐1/SRC‐3 is phosphorylated by p38MAPK. SRC‐3 phosphorylation has been correlated to an initial facilitation of RARα‐target genes activation, via the control of the dynamics of the interactions of the coactivator with RARα. Then, phosphorylation inhibits transcription via promoting the degradation of SRC‐3. In line with this, inhibition of p38MAPK markedly enhances RARα‐mediated transcription and RA‐dependent induction of cell differentiation. SRC‐3 phosphorylation and degradation occur only within the context of RARα complexes, suggesting that the RAR isotype defines a phosphorylation code through dictating the accessibility of the coactivator to p38MAPK. We propose a model in which RARα transcriptional activity is regulated by SRC‐3 through coordinated events that are fine‐tuned by RA and p38MAPK.
The study was aimed at investigating the arterial stiffness assessed by aortic pulse wave velocity (PWV) in the presence of primary hyperparathyroidism (PH), with and without concomitant hypertension. Subsequently, we examined the effect of parathyroidectomy (PTX) on arterial stiffness. A total of 28 patients with PH and concomitant hypertension, and 16 with PH without hypertension were investigated in comparison with 28 essential hypertensive patients and 18 healthy controls, respectively. Patients were matched for age, blood pressure (BP), body mass index, lipid profile and fasting glucose. Six months after PTX, 15 patients were examined again (hypertensive as well as normotensive). PWV was obtained using the SphygmoCor applanation tonometer (AtCor Medical, West Ryde, Australia). PWV was significantly higher in patients with PH and hypertension when compared with patients with essential hypertension (10.1 vs. 8.5 m s À1 , P¼0.013). PWV remained significant even after adjustment for age and BP (P¼0.02). Similarly, PWV was significantly higher in PH patients without hypertension in comparison with healthy controls (7.6 vs. 5.8 m s À1 , Po0.001). Six months after surgery, in addition to a normalization of calcium metabolism, a significant decrease in systolic BP (131 vs. 123 mm Hg, P¼0.004) and PWV (9.1 vs. 8.5 m s À1 , P¼0.024) was observed. After adjusting for BP reduction, the decrease in PWV appeared non-significant. Our data indicate that PH increases PWV as a marker of arterial stiffness, in both hypertensive and non-hypertensive patients. However, neither the calcium serum level nor the parathyroid hormone level has been associated with PWV. Specific treatment by PTX significantly decreases PWV, which may be determined primarily by improved BP control after surgery.
The peptidyl-prolyl-isomerase Pin1 interacts with phosphorylated proteins, altering their conformation. The retinoic acid receptor RARA and the acute-promyelocytic-leukemia-specific counterpart PML-RARA directly interact with Pin1. Overexpression of Pin1 inhibits ligand-dependent activation of RARA and PML-RARA. Inhibition is relieved by Pin1-targeted short interfering RNAs and by pharmacologic inhibition of the catalytic activity of the protein. Mutants of Pin1 catalytically inactive or defective for client-protein-binding activity are incapable of inhibiting ligand-dependent RARA transcriptional activity. Functional inhibition of RARA and PML-RARA by Pin1 correlates with degradation of the nuclear receptors via the proteasome-dependent pathway. In the acute myelogenous leukemia cell lines HL-60 and NB4, Pin1 interacts with RARA in a constitutive fashion. Suppression of Pin1 by a specific short hairpin RNA in HL-60 or NB4 cells stabilizes RARA and PML-RARA, resulting in increased sensitivity to the cytodifferentiating and antiproliferative activities of all-trans retinoic acid. Treatment of the two cell lines and freshly isolated acute myelogenous leukemia blasts (M1 to M4) with ATRA and a pharmacologic inhibitor of Pin1 causes similar effects. Our results add a further layer of complexity to the regulation of nuclear retinoic acid receptors and suggest that Pin1 represents an important target for strategies aimed at increasing the therapeutic index of retinoids. [Cancer Res 2009;69(3):1016-26]
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