Common Regulatory Pathways Mediate Activity of MicroRNAs Inducing Cardiomyocyte Proliferation.

Loss of functional cardiomyocytes is a major determinant of heart failure after myocardial infarction. Previous high throughput screening studies have identified a few microRNAs (miRNAs) that can induce cardiomyocyte proliferation and stimulate cardiac regeneration in mice. Here, we show that all of the most effective of these miRNAs activate nuclear localization of the master transcriptional cofactor Yes-associated protein (YAP) and induce expression of YAP-responsive genes.

Paracrine effect of regulatory T cells promotes cardiomyocyte proliferation during pregnancy and after myocardial infarction.

Cardiomyocyte proliferation stops at birth when the heart is no longer exposed to maternal blood and, likewise, to regulatory T cells (Tregs) that are expanded to promote maternal tolerance towards the fetus. Here, we report a role of Tregs in promoting cardiomyocyte proliferation. Treg-conditioned medium promotes cardiomyocyte proliferation, similar to the serum from pregnant animals.

Reversible Notch1 acetylation tunes proliferative signalling in cardiomyocytes.

Aims: The Notch signalling pathway regulates the balance between proliferation and differentiation in several tissues, including the heart. Our previous work has demonstrated that the proliferative potential of neonatal cardiomyocytes relies on Notch1 activity. A deep investigation on the biochemical regulation of the Notch signalling in cardiomyocytes is the focus of the current research.

Reversible acetylation regulates vascular endothelial growth factor receptor-2 activity.

The tyrosine kinase receptor vascular endothelial growth factor receptor 2 (VEGFR2) is a key regulator of angiogenesis. Here we show that VEGFR2 is acetylated in endothelial cells both at four lysine residues forming a dense cluster in the kinase insert domain and at a single lysine located in the receptor activation loop. These modifications are under dynamic control of the acetyltransferase p300 and two deacetylases HDAC5 and HDAC6.

GCN5-dependent acetylation of HIV-1 integrase enhances viral integration.

Background: An essential event during the replication cycle of HIV-1 is the integration of the reverse transcribed viral DNA into the host cellular genome. Our former report revealed that HIV-1 integrase (IN), the enzyme that catalyzes the integration reaction, is positively regulated by acetylation mediated by the histone acetyltransferase (HAT) p300.

Results: In this study we demonstrate that another cellular HAT, GCN5, acetylates IN leading to enhanced 3'-end processing and strand transfer activities.

Concerted action of cellular JNK and Pin1 restricts HIV-1 genome integration to activated CD4+ T lymphocytes.

Long-standing evidence indicates that quiescent human peripheral blood T lymphocytes (PBLs) do not support efficient HIV infection. In resting PBLs, reverse transcription of viral RNA takes longer than in activated cells, partially because formation of the late products of reverse transcription is decreased by RNA binding by apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G). In a subsequent step, integration of the viral complementary DNA that is eventually formed is markedly impaired.

Acetylation of HIV-1 integrase by p300 regulates viral integration.

Integration of HIV-1 into the human genome, which is catalyzed by the viral protein integrase (IN), preferentially occurs near transcriptionally active genes. Here we show that p300, a cellular acetyltransferase that regulates chromatin conformation through the acetylation of histones, also acetylates IN and controls its activity. We have found that p300 directly binds IN both in vitro and in the cells, as also specifically demonstrated by fluorescence resonance energy transfer technique analysis.

Regulation of E2F-1 after DNA damage by p300-mediated acetylation and ubiquitination.

Here we report a novel, noncompetitive mechanism that links acetylation and ubiquitination, in which the association of transcription factor E2F-1 with the cellular coactivator and acetyltransferase p300 determines its acetylation and subsequent ubiquitination. By using an antibody specifically recognizing the acetylated form of E2F-1 (AcE2F-1), we found that, after DNA damage, AcE2F-1 accumulates in the cells in a time-dependent manner, and that acetylation is increased by the expression of p300. Remarkably, the same DNA damaging conditions also induce the accumulation of ubiquitinated E2F-1, an event that is again markedly stimulated by p300 overexpression.