PARN deadenylase is involved in miRNA-dependent degradation of TP53 mRNA in mammalian cells

mRNA deadenylation is under the control of cis-acting regulatory elements, which include AU-rich elements (AREs) and microRNA (miRNA) targeting sites, within the 3′ untranslated region (3′ UTRs) of eukaryotic mRNAs. Deadenylases promote miRNA-induced mRNA decay through their interaction with miRNA-induced silencing complex (miRISC). However, the role of poly(A) specific ribonuclease (PARN) deadenylase in miRNA-dependent mRNA degradation has not been elucidated. Here, we present evidence that not only ARE- but also miRNA-mediated pathways are involved in PARN-mediated regulation of the steady state levels of TP53 mRNA, which encodes the tumor suppressor p53. Supporting this, Argonaute-2 (Ago-2), the core component of miRISC, can coexist in complexes with PARN resulting in the activation of its deadenylase activity. PARN regulates TP53 mRNA stability through not only an ARE but also an adjacent miR-504/miR-125b-targeting site in the 3′ UTR. More importantly, we found that miR-125b-loaded miRISC contributes to the specific recruitment of PARN to TP53 mRNA, and that can be reverted by the ARE-binding protein HuR. Together, our studies provide new insights into the role of PARN in miRNA-dependent control of mRNA decay and into the mechanisms behind the regulation of p53 expression

Intronic cleavage and polyadenylation regulates gene expression during DNA damage response through U1 snRNA

The DNA damage response involves coordinated control of gene expression and DNA repair. Using deep sequencing, we found widespread changes of alternative cleavage and polyadenylation site usage on ultraviolet-treatment in mammalian cells. Alternative cleavage and polyadenylation regulation in the 3ʹ untranslated region is substantial, leading to both shortening and lengthening of 3ʹ untranslated regions of genes. Interestingly, a strong activation of intronic alternative cleavage and polyadenylation sites is detected, resulting in widespread expression of truncated transcripts. Intronic alternative cleavage and polyadenylation events are biased to the 5ʹ end of genes and affect gene groups with important functions in DNA damage response and cancer. Moreover, intronic alternative cleavage and polyadenylation site activation during DNA damage response correlates with a decrease in U1 snRNA levels, and is reversible by U1 snRNA overexpression. Importantly, U1 snRNA overexpression mitigates ultraviolet-induced apoptosis. Together, these data reveal a significant gene regulatory scheme in DNA damage response where U1 snRNA impacts gene expression via the U1-alternative cleavage and polyadenylation axis

stimulating hormone

introduction: It is well recognized that there is a close relationship between TSH and PRL levels. The aim of this study was to evaluate the impact of insulin sensitivity on the association between TSH and PRL in euthyroid obese subjects.Material and Methods: Retrospective cross-sectional analysis was carried out on 165 euthyroid obese or overweight female patients. Prolactin, TSH, free thyroxine (FF4), free triiodothyronine (FF3), fasting plasma levels of insulin and glucose, postprandial levels of glucose, homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and insulin secretion (HOMA-beta cell), body weight, height, body mass index (BMI) and waist circumference were assessed. Statistical tests used were unpaired Student's t-test adjusted by Bonferroni's method and Pearson correlations with Bonferroni corrections.Results: There was no significant difference in prolactin levels between insulin sensitive and resistant subjects. Compared to insulin sensitive subjects, TSH levels were higher in insulin resistant subjects but it was not statistically significant. We observed significant positive correlation between prolactin and TSH in insulin sensitive and normoglycemic subjects (r=0.273, p=0.039 and r=0.253, p=0.023, respectively) but this correlation was lost in insulin resistant subjects and subjects who had fasting glucose levels 100mg/dl (r=0.057, p=0.609 and r=0.090, p=0.404, respectively).Conclusions: The findings of this study provide some clues about the relationship between PRL and TSH in insulin sensitive obese subjects. The insulin sensitivity and carbohydrate homeostasis seem to be involved in relationship with PRL and TSH by the brain via serotoninergic and dopaminergic system

Impact of insulin sensitivity in relationship with prolactin and thyroid stimulating hormone.

INTRODUCTION: It is well recognized that there is a close relationship between TSH and PRL levels. The aim of this study was to evaluate the impact of insulin sensitivity on the association between TSH and PRL in euthyroid obese subjects. MATERIAL AND METHODS: Retrospective cross-sectional analysis was carried out on 165 euthyroid obese or overweight female patients. Prolactin, TSH, free thyroxine (FT4), free triiodothyronine (FT3), fasting plasma levels of insulin and glucose, postprandial levels of glucose, homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and insulin secretion (HOMA-beta cell), body weight, height, body mass index (BMI) and waist circumference were assessed. Statistical tests used were unpaired Student's t-test adjusted by Bonferroni's method and Pearson correlations with Bonferroni corrections. RESULTS: There was no significant difference in prolactin levels between insulin sensitive and resistant subjects. Compared to insulin sensitive subjects, TSH levels were higher in insulin resistant subjects but it was not statistically significant. We observed significant positive correlation between prolactin and TSH in insulin sensitive and normoglycemic subjects (r=0.273, p=0.039 and r=0.253, p=0.023, respectively) but this correlation was lost in insulin resistant subjects and subjects who had fasting glucose levels >or=100 mg/dl (r=0.057, p=0.609 and r=0.090, p=0.404, respectively). CONCLUSIONS: The findings of this study provide some clues about the relationship between PRL and TSH in insulin sensitive obese subjects. The insulin sensitivity and carbohydrate homeostasis seem to be involved in relationship with PRL and TSH by the brain via serotoninergic and dopaminergic system