Biomedical subjects

I Uribesalgo

Publications and source records attributed to I Uribesalgo.

3 recordsLinked to original sources

PubMed2006

PML4 induces differentiation by Myc destabilization.

Opposing functions like oncogene and tumor suppressions have been established for c-Myc and promyelocytic leukemia (PML) protein, respectively. Myc is known to inhibit differentiation of hematopoietic precursor cells, and here we report that PML promotes cell differentiation. We further demonstrate that PML and Myc form a complex in vivo. The interaction of the two proteins leads to the destabilization of Myc in a manner dependent on the really interesting new gene (RING) domain of PML. Although several PML isoforms are able to interact with Myc, the ability to destabilize Myc is specific for PML4. Importantly, the PML-induced destabilization resulted in a reduction of promoter-bound Myc on Myc-repressed genes. Thereby, PML induced the re-activation of Myc-repressed target genes including the tumor suppressive genes of the cell cycle inhibitors cdkn1a/p21 and cdkn2b/p15. Together, these results establish PML-mediated destabilization of Myc and the derepression of cell cycle inhibitor genes as an important regulatory mechanism that allows cell differentiation and prevents aberrant proliferation driven by uncontrolled Myc activity.

Cell Differentiation↗

PubMed2005

Lack of oestrogen protection in amyloid-mediated endothelial damage due to protein nitrotyrosination.

Amyloid beta-peptide (Abeta) cytotoxicity, the hallmark of Alzheimer's disease, implicates oxidative stress in both neurons and vascular cells, particularly endothelial cells. Consequently, antioxidants have shown neuroprotective activities against Abeta-induced cytotoxicity. Among the different antioxidants used in both in vitro and in vivo studies, 17beta-oestradiol (E2) has garnered the most attention. Oestrogen attenuated Abeta(E22Q)-induced toxicity in neurons but failed to protect endothelial cells. Here we show that E2-mediated activation of endothelial nitric oxide synthase (eNOS) increases the production of nitric oxide (NO), which, under Abeta(E22Q)-induced oxidative damage, results in the formation of peroxynitrite and increased nitration of tyrosine residues. Inhibition of eNOS prevents nitrotyrosination and permits E2-mediated protection against Abeta(E22Q) on endothelial cells. The main nitrotyrosinated proteins in the presence of E2 and Abeta(E22Q) were identified by MALDI-TOF mass spectrometry. These proteins are key players in the regulation of energy production, cytoskeletal integrity, protein metabolism and protection against oxidative stress. Our data highlight the potential damaging consequences of E2 in vascular disorders dealing with oxidative stress conditions, such as cerebral amyloid angiopathy, stroke and ischaemia-reperfusion conditions.

Aged↗

PubMed2005

The physiology and pathophysiology of nitric oxide in the brain.

Nitric oxide (NO) is a molecule with pleiotropic effects in different tissues. NO is synthesized by NO synthases (NOS), a family with four major types: endothelial, neuronal, inducible and mitochondrial. They can be found in almost all the tissues and they can even co-exist in the same tissue. NO is a well-known vasorelaxant agent, but it works as a neurotransmitter when produced by neurons and is also involved in defense functions when it is produced by immune and glial cells. NO is thermodynamically unstable and tends to react with other molecules, resulting in the oxidation, nitrosylation or nitration of proteins, with the concomitant effects on many cellular mechanisms. NO intracellular signaling involves the activation of guanylate cyclase but it also interacts with MAPKs, apoptosis-related proteins, and mitochondrial respiratory chain or anti-proliferative molecules. It also plays a role in post-translational modification of proteins and protein degradation by the proteasome. However, under pathophysiological conditions NO has damaging effects. In disorders involving oxidative stress, such as Alzheimer's disease, stroke and Parkinson's disease, NO increases cell damage through the formation of highly reactive peroxynitrite. The paradox of beneficial and damaging effects of NO will be discussed in this review.

Animals↗