The RNA-binding and adaptor protein Sam68 modulates signal-dependent splicing and transcriptional activity of the androgen receptor

2008 ◽  
Vol 215 (1) ◽  
pp. 67-77 ◽  
Author(s):  
P Rajan ◽  
L Gaughan ◽  
C Dalgliesh ◽  
A El-Sherif ◽  
CN Robson ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Transcriptional Activity ◽  
Rna Binding ◽  
Adaptor Protein

scholarly journals Lysine acetyltransferase Tip60 acetylates the APP adaptor Fe65 to increase its transcriptional activity

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Sabine Probst ◽  
Florian Riese ◽  
Larissa Kägi ◽  
Maik Krüger ◽  
Natalie Russi ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Target Genes ◽  
Adaptor Protein ◽  
Proteolytic Processing ◽  
Class Iii ◽  
Lysine Deacetylase ◽  
Lysine Residues ◽  
Lysine Acetyltransferase ◽  
Complex Forms ◽  
Spot Formation

AbstractProteolytic processing of the amyloid precursor protein (APP) releases the APP intracellular domain (AICD) from the membrane. Bound to the APP adaptor protein Fe65 and the lysine acetyltransferase (KAT) Tip60, AICD translocates to the nucleus. Here, the complex forms spherical condensates at sites of endogenous target genes, termed AFT spots (AICD-Fe65-Tip60). We show that loss of Tip60 KAT activity prevents autoacetylation, reduces binding of Fe65 and abolishes Fe65-mediated stabilization of Tip60. Autoacetylation is a prerequisite for AFT spot formation, with KAT-deficient Tip60 retained together with Fe65 in speckles. We identify lysine residues 204 and 701 of Fe65 as acetylation targets of Tip60. We do not detect acetylation of AICD. Mutation of Fe65 K204 and K701 to glutamine, mimicking acetylation-induced charge neutralization, increases the transcriptional activity of Fe65 whereas Tip60 inhibition reduces it. The lysine deacetylase (KDAC) class III Sirt1 deacetylates Fe65 and pharmacological modulation of Sirt1 activity regulates Fe65 transcriptional activity. A second acetylation/deacetylation cycle, conducted by CBP and class I/II KDACs at different lysine residues, regulates stability of Fe65. This is the first report describing a role for acetylation in the regulation of Fe65 transcriptional activity, with Tip60 being the only KAT tested that supports AFT spot formation.

scholarly journals Sam68 promotes hepatic gluconeogenesis via CRTC2

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aijun Qiao ◽  
Junlan Zhou ◽  
Shiyue Xu ◽  
Wenxia Ma ◽  
Chan Boriboun ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Therapeutic Target ◽  
Rna Binding ◽  
Adaptor Protein ◽  
Diabetic Mouse ◽  
Mrna Levels ◽  
Hepatic Gluconeogenesis ◽  
Kinase Substrate ◽  
Glucose Levels ◽  
Patients With Diabetes

AbstractHepatic gluconeogenesis is essential for glucose homeostasis and also a therapeutic target for type 2 diabetes, but its mechanism is incompletely understood. Here, we report that Sam68, an RNA-binding adaptor protein and Src kinase substrate, is a novel regulator of hepatic gluconeogenesis. Both global and hepatic deletions of Sam68 significantly reduce blood glucose levels and the glucagon-induced expression of gluconeogenic genes. Protein, but not mRNA, levels of CRTC2, a crucial transcriptional regulator of gluconeogenesis, are >50% lower in Sam68-deficient hepatocytes than in wild-type hepatocytes. Sam68 interacts with CRTC2 and reduces CRTC2 ubiquitination. However, truncated mutants of Sam68 that lack the C- (Sam68ΔC) or N-terminal (Sam68ΔN) domains fails to bind CRTC2 or to stabilize CRTC2 protein, respectively, and transgenic Sam68ΔN mice recapitulate the blood-glucose and gluconeogenesis profile of Sam68-deficient mice. Hepatic Sam68 expression is also upregulated in patients with diabetes and in two diabetic mouse models, while hepatocyte-specific Sam68 deficiencies alleviate diabetic hyperglycemia and improves insulin sensitivity in mice. Thus, our results identify a role for Sam68 in hepatic gluconeogenesis, and Sam68 may represent a therapeutic target for diabetes.

scholarly journals RanBPM, a Nuclear Protein That Interacts with and Regulates Transcriptional Activity of Androgen Receptor and Glucocorticoid Receptor

2002 ◽  
Vol 277 (50) ◽  
pp. 48020-48027 ◽  
Author(s):  
Mira A. Rao ◽  
Helen Cheng ◽  
Alandra N. Quayle ◽  
Hideo Nishitani ◽  
Colleen C. Nelson ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Glucocorticoid Receptor ◽  
Transcriptional Activity ◽  
Nuclear Protein

scholarly journals The SRSF4-GAS5-Glucocorticoid Receptor Axis Regulates Ventricular Hypertrophy

2021 ◽  
Author(s):  
Javier Larrasa-Alonso ◽  
María Villalba ◽  
Carlos Martí-Gómez ◽  
Paula Ortiz-Sánchez ◽  
Marina López-Olañeta ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Cardiac Hypertrophy ◽  
Diastolic Dysfunction ◽  
Ventricular Hypertrophy ◽  
Transcriptional Activity ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Left Ventricular ◽  
Therapeutic Tools ◽  
Nucleotide Resolution

Rationale: RNA-binding proteins (RBPs) play critical roles in human biology and disease. Aberrant RBP expression affects various steps in RNA processing, altering the function of the target RNAs. The RBP serine/arginine-rich splicing factor 4 (SRSF4) has been linked to neuropathies and cancer. However, its role in the heart is completely unknown. Objective: To investigate the role of SRSF4 in the heart. Methods and Results: Echocardiography of mice specifically lacking SRSF4 in the heart (SRSF4 KO) revealed left ventricular hypertrophy and increased cardiomyocyte area, which led to progressive diastolic dysfunction with age. SRSF4 KO mice showed altered electrophysiological activity under isoproterenol-induced cardiac stress, with a post-QRS depression and a longer QT interval, indicating an elevated risk of sudden cardiac death. RNA-Seq analysis revealed expression changes in several long non-coding RNAs (lncRNAs), including GAS5 (growth arrest specific 5), which we identified as a direct SRSF4 target in cardiomyocytes by individual-nucleotide-resolution cross-linking and immuno-precipitation (iCLIP). GAS5 is a repressor of the glucocorticoid receptor (GR) and was downregulated in SRSF4 KO hearts. This corresponded with elevated GR transcriptional activity in cardiomyocytes, leading to increases in hypertrophy markers and cell size. Furthermore, hypertrophy in SRSF4 KO cardiomyocytes was reduced by overexpressing GAS5. Conclusions: Loss of SRSF4 expression results in cardiac hypertrophy, diastolic dysfunction, and abnormal repolarization. The molecular mechanism underlying this effect involves GAS5 downregulation and consequent elevation of GR transcriptional activity. Our findings may help to develop new therapeutic tools for the treatment of cardiac hypertrophy and myocardial pathology in Cushing's syndrome patients.

scholarly journals Molecular Interplay between AURKA and SPOP Dictates CRPC Pathogenesis via Androgen Receptor

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3247
Author(s):  
Kumar Nikhil ◽  
Mohini Kamra ◽  
Asif Raza ◽  
Hanan S. Haymour ◽  
Kavita Shah
Keyword(s):  
Androgen Receptor ◽  
Feedback Loop ◽  
Adaptor Protein ◽  
Castration Resistant Prostate Cancer ◽  
Wild Type ◽  
Protein Levels ◽  
Upstream Regulator ◽  
Castration Resistant ◽  
Tumor Enhancer

SPOP, an adaptor protein for E3 ubiquitin ligase can function as a tumor-suppressor or a tumor-enhancer. In castration-resistant prostate cancer (CRPC), it inhibits tumorigenesis by degrading many oncogenic targets, including androgen receptor (AR). Expectedly, SPOP is the most commonly mutated gene in CRPC (15%), which closely correlates with poor prognosis. Importantly, 85% of tumors that retain wild-type SPOP show reduced protein levels, indicating that SPOP downregulation is an essential step in CRPC progression. However, the underlying molecular mechanism remains unknown. This study uncovered the first mechanism of SPOP regulation in any type of cancer. We identified SPOP as a direct substrate of Aurora A (AURKA) using an innovative technique. AURKA directly phosphorylates SPOP at three sites, causing its ubiquitylation. SPOP degradation drives highly aggressive oncogenic phenotypes in cells and in vivo including stabilizing AR, ARv7 and c-Myc. Further, SPOP degrades AURKA via a feedback loop. SPOP upregulation is one of the mechanisms by which enzalutamide exerts its efficacy. Consequently, phospho-resistant SPOP fully abrogates tumorigenesis and EMT in vivo, and renders CRPC cells sensitive to enzalutamide. While genomic mutations of SPOP can be treated with gene therapy, identification of AURKA as an upstream regulator of SPOP provides a powerful opportunity for retaining WT-SPOP in a vast majority of CRPC patients using AURKA inhibitors ± enzalutamide, thereby treating the disease and inhibiting its progression.

scholarly journals Cooperative Interactions between Androgen Receptor (AR) and Heat-Shock Protein 27 Facilitate AR Transcriptional Activity

2007 ◽  
Vol 67 (21) ◽  
pp. 10455-10465 ◽  
Author(s):  
Amina Zoubeidi ◽  
Anousheh Zardan ◽  
Eliana Beraldi ◽  
Ladan Fazli ◽  
Richard Sowery ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Transcriptional Activity ◽  
Heat Shock Protein 27 ◽  
Cooperative Interactions

Ethanolic extract of Algerian propolis decreases androgen receptor transcriptional activity in cultured LNCaP cells

2019 ◽  
Vol 189 ◽  
pp. 108-115 ◽  
Author(s):  
Nada Zabaiou ◽  
Allan Fouache ◽  
Amalia Trousson ◽  
Julio Buñay-Noboa ◽  
Geoffroy Marceau ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Transcriptional Activity ◽  
Ethanolic Extract ◽  
Lncap Cells
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