Search

Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor and about 50% of cases have the CRTC1-MAML2 translocation. The CREB pathway has been associated with the transforming activity of CRTC1-MAML2. The aim of this study was to determine the effects of CREB inhibition on MECs cells' behavior in vitro. Three MEC cell lines (UM-HMC-2, H292, H253) were treated with the CREB-inhibitor, 666.15. Drug IC50 doses were determined for each cell line and CREB-inhibition was confirmed through mRNA levels of downstream target NURR1. Clonogenic and sphere assays were used to assess survival and percentage of cancer stem cells (CSC) and transwell and scratch assays were to evaluate the cells' invasive and migratory capacity. CREB-inhibition was confirmed by reduced transcript levels of NURR1. The drug significantly delayed cell invasion. The number of surviving colonies was also significantly reduced following drug exposure. CREB inhibition efficiently impaired MEC key oncogenic behavior associated with metastasis and drug resistance, such as cell invasion and survival respectively. This study was supported by FAPESP (2019/26676-6 and 2021/10810-6). [ABSTRACT FROM AUTHOR]

Studies on the interaction of HIV with host factors have recently highlighted a potential role in the pathogenesis of AIDS for three distinct members of the whey acidic protein (WAP) family, secretory leukocyte protease inhibitor, Elafin, and ps20. Identified by an evolutionarily conserved canonical four-disulphide structural domain [whey four disulphide core domain (WFDC)], WAP proteins are increasingly being shown to display functions beyond both protease inhibition and anti-infective activity, to which they were originally ascribed. We propose novel mechanisms on why this might be the case based on an analysis of the structure-function of its human members. Our analysis suggests that the interaction of HIV with WAP proteins might unravel unknown functions of the ancient WFDC and inform novel immunotherapies for the treatment of HIV and broader virus infections. [Copyright &y& Elsevier]

The innate immune response is of pivotal importance in defending the mucosal barriers of the body against pathogenic attack. The list of proteins that contribute to this defense mechanism is constantly being updated. In this review we introduce a novel family of secreted proteins, palate, lung, and nasal epithelium clones (PLUNCs), that are expressed in the mouth, nose and upper airways of humans, mice, rats and cows. In humans, PLUNC genes are located in a compact cluster on chromosome 20, with similar loci being found in synteneic locations in other species. The protein products of this gene cluster are predicted to be structural homologues of the human lipopolysaccharide binding proteins, lipopolysaccharide binding-protein (LBP) and bacterial permeability-increasing protein (BPI), which are known mediators of host defense against Gram-negative bacteria. On the basis of these observations we outline why we believe PLUNC proteins mediate host defense functions in the oral, nasal and respiratory epithelia. [Copyright &y& Elsevier]

Until recently, two key members of the innate immune response to Gram negative bacteria, bactericidal permeability-increasing protein (BPI) and lipopolysaccharide (LPS)-binding protein (LBP), have been considered to be members of a small family of lipid-binding proteins that also contains cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP). A recent paper has characterised three related proteins that are expressed in the mouth, nose and upper airways. Taken together with other recent data, it is clear that a large family of such proteins exists and these additional members might also function in the innate immune response. [Copyright &y& Elsevier]

Abstract: Palate, lung and nasal epithelial clone (PLUNC) proteins are structural homologues to the innate defence molecules LPS-binding protein (LBP) and bactericidal/permeability-increasing protein (BPI). PLUNCs make up the largest portion of the wider BPI/LBP/PLUNC-like protein family and are amongst the most rapidly evolving mammalian genes. In this study we systematically identified and characterised BPI/LBP/PLUNC-like protein-encoding genes in the chicken genome. We identified eleven complete genes (and a pseudogene). Five of them are clustered on a >50kb locus on chromosome 20, immediately adjacent to BPI. In addition to BPI, we have identified presumptive orthologues LPLUNCs 2, 3, 4 and 6, and BPIL-2. We find no evidence for the existence of single domain containing proteins in birds. Strikingly our analysis also suggests that there is no LBP orthologue in chicken. This observation may in part account for the relative resistance to LPS toxicity observed in birds. Our results indicate significant differences between the avian and mammalian repertoires of BPI/LBP/PLUNC-like genes at the genomic and transcriptional levels and provide a framework for further functional analyses of this gene family in chickens. [Copyright &y& Elsevier]

Bid, a BH3-only Bcl-2 protein, is activated by proteolytic cleavage exposing the BH3 domain, which then induces apoptosis by interacting with pro-apoptotic Bcl-2 family proteins (e.g. Bax and Bak) at the mitochondrial surface. The arrangement of domains within Bid suggested that Bid function might be regulated in part by alternative splicing. We have determined the gene structure of human Bid and identified a number of novel exons. We have also demonstrated endogenous mRNA and protein expression for three novel isoforms of Bid, generated using these exons. Bid[sub S] contains the N-terminal regulatory domains of Bid without the BH3 domain; Bid[sub EL] corresponds to full-length Bid with additional N-terminal sequence; and Bid[sub ES] contains only the Bid sequence downstream of the BH3 domain. Expression of these isoforms is regulated during granulocyte maturation. In functional studies Bid[sub EL] induces apoptosis, whereas Bids abrogates the pro-apoptotic effects of truncated Bid and inhibits Fas-mediated apoptosis. Bid[sub ES] induces apoptosis but is also able to partially inhibit the pro-apoptotic effects of truncated Bid. These three novel endogenously expressed isoforms of Bid are distinct in their expression, their cellular localization, and their effects upon cellular apoptosis. Differential expression of these novel Bid isoforms may regulate the function of Bid following cleavage and thus influence the fate of cells exposed to a range of pro-apoptotic stimuli. [ABSTRACT FROM AUTHOR]