SEL1L a multifaceted protein playing a role in tumor progression

Abstract

Since the cloning in 1997 of SEL1L, the human ortholog of the sel-1 gene of C. elegans, most studies have focused on its role in cancer progression and have provided significant evidences to link its increased expression to a decrease in tumor aggressiveness. SEL1L resides on a ''Genome Desert area'' on chromosome 14q24.3-31 and is highly conserved in evolution. The function of the SEL1L encoded protein is still very elusive although, several evidences from lower organisms indicate that it plays a major role in protein degradation using the ubiquitin-proteosome system. SEL1L has a very complex structure made up of modules: genomically it consists of 21 exons featuring several alternative transcripts encoding for putative protein isoforms. This structural complexity ensures protein flexibility and specificity, indeed the protein was found in different sub-cellular compartments and may turn on a particular transcript in response to specific stimuli. The overall architecture of SEL1L guarantees an exquisite regulation in the expression of the gene.

Deficiency of Suppressor Enhancer Lin12 1 Like (SEL1L) in Mice Leads to Systemic Endoplasmic Reticulum Stress and Embryonic Lethality

“…Nevertheless, it is possible the partial SEL1L peptide has other cellular function(s). Additionally, the mammalian Sel1l gene expresses multiple transcripts derived through alternative splicing among exons in the 5Ј and 3Ј ends of the gene (27). Indeed, our Northern analysis has detected at least two smaller transcripts in the mutant embryos.…”

“…Activated ATF6 translocates to the nucleus where it binds to the ER stress responsive element in genes encoding ER chaperone proteins (25,26). SEL1L (suppressor enhancer Lin12 1 like) is a widely expressed ER membrane protein (type I) with a complex domain structure (27). Biochemical and molecular studies in vitro revealed that in eukaryotic cells SEL1L nucleates an ER membrane protein complex that is required for dislocation of unfolded or misfolded proteins from the ER lumen into the cytosol for degradation (28 -33).…”

Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival

“…Nonetheless, studies have implicated Sel1L in various cellular processes, including tumorigenesis of various cancer types (31), stem cell differentiation (32), pancreatic epithelial cell differentiation (33), and retrotranslocation of cholera toxin to the cytosol (26). Variants in the Sel1L gene have been identified in human patients with autoimmune thyroid diseases (34), in canines with progressive early-onset cerebellar ataxia (35), and in humans with Alzheimer's disease (36).…”

Down-modulation of SEL1L, an Unfolded Protein Response and Endoplasmic Reticulum-associated Degradation Protein, Sensitizes Glioma Stem Cells to the Cytotoxic Effect of Valproic Acid

“…Here we explore the potential therapeutic advantages of VPA treatment combined with perturbation of the proteostasis network on GSC by targeting SEL1L, a crucial modulator of homeostasis (15)(16)(17)43) and linked to neural stemness maintenance and lineage determination (18) as well as cancer aggressiveness (19,21,43).…”