PubMed · 8648324
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E Nobile-Orazio. 1996. Multifocal motor neuropathy.. https://doi.org/10.1136/jnnp.60.6.599
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In glioblastoma (GBM), the most frequent and lethal brain tumor, therapies suppressing recurrently altered signaling pathways failed to extend survival. However, in patient subsets, specific genetic lesions can confer sensitivity to targeted agents. By exploiting an integrated model based on patient-derived stem-like cells, faithfully recapitulating the original GBMs in vitro and in vivo, here, we identify a human GBM subset (∼9% of all GBMs) characterized by ERBB3 overexpression and nuclear accumulation. ERBB3 overexpression is driven by inheritable promoter methylation or post-transcriptional silencing of the oncosuppressor miR-205 and sustains the malignant phenotype. Overexpressed ERBB3 behaves as a specific signaling platform for fibroblast growth factor receptor (FGFR), driving PI3K/AKT/mTOR pathway hyperactivation, and overall metabolic upregulation. As a result, ERBB3 inhibition by specific antibodies is lethal for GBM stem-like cells and xenotransplants. These findings highlight a subset of patients eligible for ERBB3-targeted therapy.
p73, unlike p53, is expressed as a number of isomeric forms. Alternative splicing at the 3' end of p73 transcript, together with the usage of a second promoter downstream of exon 3, can generate up to 24 p73 isoforms. Variants lacking the TA domain (DeltaN isoforms) are induced by TAp73 and by p53, and inhibit their transcriptional activity. However, understanding the complex biology of p73 has been handicapped by the lack of high affinity specific antibodies for the different isoforms. Here, we report the characterization, by Western blotting and immunoprecipitation, of three new polyclonal antisera recognizing all p73 isoforms, only DeltaN isoforms or only p73alpha, and which have advantages of affinity and specificity over previously available antibodies.
The norepinephrine transporter (NET) is a membrane protein responsible for transporting extracellular norepinephrine. The cocaine and tricyclic antidepressant-sensitive NET belongs to a family of sodium and chloride coupled transporters that include the monoamines dopamine and serotonin and the amino acids GABA and glycine. The regional distribution of the NET has been defined by synaptosomal uptake of norepinephrine and by autoradiographic approaches in rodent and primate brain. However, the NET has not been well characterized in the human brain due to the overall low abundance of protein expressed in axon terminals. Recently, immunolocalization studies have been used to identify the regional distribution of the cytoplasmic NET epitope in rodent brain. We report here on the characteristics of drug interactions with the native NET protein in human postmortem brain. Antisera raised against a 17-amino acid peptide from the N-terminus of the hNET recognized an 80 kDa species in human cerebral cortex. Chronic exposure to cocaine upregulated NET protein expression and [3H]nisoxetine binding sites in the insular cortex from brains of cocaine addicts. These results demonstrate that immunologic and radioligand binding approaches afford specific labeling of the native transport protein in postmortem human brain.