Gene expression analysis in peripheral blood cells of patients with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC): identification of NRF2 pathway activation.

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare disease that is inherited in an autosomal dominant manner. Affected patients may develop from cutaneous and uterine leiomyomas to type 2 papillary renal cell carcinoma (Schmidt and Linehan, Int J Nephrol Renovasc Dis 7:253-260, 2014). HLRCC is caused by germline mutations in the FH gene, which produces the fumarate hydratase protein that participates in the tricarboxylic acid cycle during the conversion of fumarate to malate. In FH-deficient cells, high concentrations of fumarate lead to a series of intricate events, which seem to be responsible for the malignant transformation (Yang et al., J Clin Invest 123(9):3652-3658, 2013) (Bardella et al., J Pathol 225(1):4-11, 2011). Among these events, one that is gaining attention is the pathological activation of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which has been found in several types of cancer and is implicated in the expression of genes associated with antioxidant responses (Linehan and Rouault, Clin Cancer Res 19(13):3345-3352, 2013). In this article, we present the results of a gene expression analysis performed on peripheral blood cells from patients with HLRCC syndrome, where upregulation of numerous NRF2 targets and the differential expression of two key genes, Jun dimerization protein 2 (JDP2) and Phosphoglycerate mutase family member 5 (PGAM5), which are involved in the control of this pathway, was observed.

The protein interactome of collapsin response mediator protein-2 (CRMP2/DPYSL2) reveals novel partner proteins in brain tissue.

PURPOSE: Collapsin response mediator protein-2 (CRMP2) is a CNS protein involved in neuronal development, axonal and neuronal growth, cell migration, and protein trafficking. Recent studies have linked perturbations in CRMP2 function to neurodegenerative disorders such as Alzheimer's disease, neuropathic pain, and Batten disease, and to psychiatric disorders such as schizophrenia. Like most proteins, CRMP2 functions though interactions with a molecular network of proteins and other molecules. EXPERIMENTAL DESIGN: Here, we have attempted to identify additional proteins of the CRMP2 interactome to provide further leads about its roles in neurological functions. We used a combined co-immunoprecipitation and shotgun proteomic approach in order to identify CRMP2 protein partners. RESULTS: We identified 78 CRMP2 protein partners not previously reported in public protein interaction databases. These were involved in seven biological processes, which included cell signaling, growth, metabolism, trafficking, and immune function, according to Gene Ontology classifications. Furthermore, 32 different molecular functions were found to be associated with these proteins, such as RNA binding, ribosomal functions, transporter activity, receptor activity, serine/threonine phosphatase activity, cell adhesion, cytoskeletal protein binding and catalytic activity. In silico pathway interactome construction revealed a highly connected network with the most overrepresented functions corresponding to semaphorin interactions, along with axon guidance and WNT5A signaling. CONCLUSIONS AND CLINICAL RELEVANCE: Taken together, these findings suggest that the CRMP2 pathway is critical for regulating neuronal and synaptic architecture. Further studies along these lines might uncover novel biomarkers and drug targets for use in drug discovery.