IRE1α is an endoplasmic reticulum (ER) transmembrane protein with cytoplasmic kinase and endoribonuclease (RNase) domains. Under ER stress, IRE1α can splice Xbp1 mRNA enabling translation of this unfo Show more
IRE1α is an endoplasmic reticulum (ER) transmembrane protein with cytoplasmic kinase and endoribonuclease (RNase) domains. Under ER stress, IRE1α can splice Xbp1 mRNA enabling translation of this unfolded protein response transcription factor or mediate sequence-specific degradation of mRNAs through regulated IRE1α-dependent decay (RIDD). Somatic mutations in IRE1α occur in many different human cancers including non-melanoma skin cancer (NMSC). To understand their role in skin cancer pathogenesis, we generated immortalized primary mouse keratinocytes with inducible expression of multiple engineered and cancer-associated mutations, including those present in NMSC. All NMSC mutations tested were activating mutations with elevated autophosphorylation and enhanced RIDD activity relative to the degree of change seen in Xbp1 splicing. Pathway analysis of RNA-Seq data and in vitro studies showed that RNase-impaired mutations enhanced cell migration due to increased levels of active RhoA and the RIDD target Angptl4. In contrast, activating mutations caused elevated Rac1 activation, enrichment of genes involved in DNA repair, increased phospho-ATR levels and improved survival in response to UVB irradiation, a crucial etiological factor for sun-exposure-induced skin cancers. Together, these results suggest divergent roles of IRE1α mutations that mediate crucial tumor-promoting events in keratinocytes. Show less
Increasing evidence indicates that β-secretase 1 (BACE1) activity and concentration in blood are candidate biomarkers for Alzheimer's disease (AD). Investigating potential demographic, biological, and Show more
Increasing evidence indicates that β-secretase 1 (BACE1) activity and concentration in blood are candidate biomarkers for Alzheimer's disease (AD). Investigating potential demographic, biological, and clinical determinants of BACE1 in the blood matrix is the critical step to validate and qualify BACE1 bio-indicators for different contexts-of-use (CoU), such as risk assessment, early detection, diagnosis, prognosis, management of AD, and outcome of amyloid pathway targeted drugs. To evaluate the influence of age, sex, HDL-cholesterol and comorbidities (cardiovascular diseases, hypertension, diabetes) on circulating BACE-1 activity. prospective analysis of serum samples, clinical, biological, and demographic variables. Three cohorts: 1) Memory Clinic of the Department of Internal Medicine, S. Anna University Hospital, Ferrara (Italy); 2) outpatients attending the Menopause and Osteoporosis Centre (MOC) of the University of Ferrara (Ferrara, Italy); 3) Prevention Center of the University of Ferrara. 504 cognitively healthy individuals (median age: 62 years, interquartile range: 51-73) and 175 patients with AD (78 years, 74-82). serum BACE1 (sBACE1), age, sex, HDL-cholesterol, major comorbidities. Age was the strongest independent predictor of sBACE1 variance (β=0.425, p<0.0001), followed by sex (β=0.180, p<0.0001), high density lipoprotein-cholesterol (HDL-C) (β=-0.168, p<0.0001) and hypertension (β=0.111, p<0.05) (overall model, R2: 0.232). The probability of having elevated sBACE1 activity increased after 70 years of age, with women being more susceptible to higher sBACE1 activity than men. We provide evidence about potential clinical and biological determinants of sBACE1 activity with a strong association among biomarker, female sex, and older age. Show less