Identification of a region within SEL1L protein required for tumour growth inhibition

Cattaneo, Monica; Canton, Cristina; Albertini, Alberto; Biunno, Ida

doi:10.1016/j.gene.2003.10.021

Cited by 22 publications

(21 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The gene trap Sel1l allele is predicted to generate a partial Sel1l peptide that lacks the carboxyl-terminal 329 amino acids. The truncated region contains several highly conserved motifs/domains that were shown to be critical for suppression of tumor cell growth (48). We have demonstrated that transient expression of the partial Sel1l peptide fails to rescue the ERAD and protein secretory defects in Sel1l Ϫ/Ϫ MEF cells (see Figs.…”

Section: Discussionmentioning

confidence: 89%

“…Of the 469 offspring obtained from intercrossing Sel1l ϩ/Ϫ mice, no homozygous mutant (Sel1l Ϫ/Ϫ ) was found, suggesting that disruption of SEL1L function causes embryonic lethality (Fig. 1F) (48), suggesting that some homozygous mutants were dead before E11.5. Nearly 95% of the homozygous mutant embryos at E12.5 were significantly smaller than their wild-type or heterozygous littermates.…”

Section: Sel1l Function Is Essential For Early Mouse Embryonicmentioning

confidence: 99%

See 1 more Smart Citation

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

Francisco

Singh

et al. 2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Stress in the endoplasmic reticulum (ER) plays an important causal role in the pathogenesis of several chronic diseases such as Alzheimer, Parkinson, and diabetes mellitus. Insight into the genetic determinants responsible for ER homeostasis will greatly facilitate the development of therapeutic strategies for the treatment of these debilitating diseases. Suppressor enhancer Lin12 1 like (SEL1L) is an ER membrane protein and was thought to be involved in the quality control of secreted proteins. Here we show that the mice homozygous mutant for SEL1L were embryonic lethal. Electron microscopy studies revealed a severely dilated ER in the fetal liver of mutant embryos, indicative of alteration in ER homeostasis. Consistent with this, several ER stress responsive genes were significantly up-regulated in the mutant embryos. Mouse embryonic fibroblast cells deficient in SEL1L exhibited activated unfolded protein response at the basal state, impaired ER-associated protein degradation, and reduced protein secretion. Furthermore, markedly increased apoptosis was observed in the forebrain and dorsal root ganglions of mutant embryos. Taken together, our results demonstrate an essential role for SEL1L in protein quality control during mouse embryonic development.

show abstract

Section: Discussionmentioning

confidence: 89%

Section: Sel1l Function Is Essential For Early Mouse Embryonicmentioning

confidence: 99%

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

Francisco

Singh

et al. 2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…The mammalian homolog of Hrd3p, SEL1L (32), is predicted to be a type I membrane protein with five N-linked glycans and a molecular mass of Ϸ100 kDa. SEL1L is highly expressed in the pancreas and is implicated in cell growth in a variety of tissue culture systems (32)(33)(34). Sel-1 RNA interference in C. elegans induces ER stress, as measured by using a strain that is transgenic for an unfolded protein response reporter construct (35), but a role for SEL1L in mammalian ER degradation as well as a physical association of SEL1L with HRD1 have yet to be shown.…”

Section: Resultsmentioning

confidence: 99%

Multiprotein complexes that link dislocation, ubiquitination, and extraction of misfolded proteins from the endoplasmic reticulum membrane

Lilley

Ploegh²

2005

Proc. Natl. Acad. Sci. U.S.A.

295

345

View full text Add to dashboard Cite

Polypeptides that fail to pass quality control in the endoplasmic reticulum (ER) are dislocated from the ER membrane to the cytosol where they are degraded by the proteasome. Derlin-1, a member of a family of proteins that bears homology to yeast Der1p, was identified as a factor that is required for the human cytomegalovirus US11-mediated dislocation of class I MHC heavy chains from the ER membrane to the cytosol. Derlin-1 acts in concert with the AAA ATPase p97 to remove dislocation substrate proteins from the ER membrane, but it is unknown whether other factors aid Derlin-1 in its function. Mammalian genomes encode two additional, related proteins (Derlin-2 and Derlin-3). The similarity of the mammalian Derlin-2 and Derlin-3 proteins to yeast Der1p suggested that these as-yet-uncharacterized Derlins also may play a role in ER protein degradation. We demonstrate here that Derlin-2 is an ER-resident protein that, similar to Derlin-1, participates in the degradation of proteins from the ER. Furthermore, we show that Derlin-2 forms a robust multiprotein complex with the p97 AAA ATPase as well as the mammalian orthologs of the yeast Hrd1p͞ Hrd3p ubiquitin-ligase complex. The data presented here define a set of interactions between proteins involved in dislocation of misfolded polypeptides from the ER.Derlin ͉ HRD1 ͉ SEL1L ͉ p97 ͉ VIMP

show abstract

“…Alternative splicing events at the 3Ј ends generate a tail of 9 amino acid residues (GIYVSPFTF) in SEL1L-B (10) and an SRL sequence, variant of the conserved peroxisomal targeting signal SKL, in SEL1L-C (9,10). A fibronectin type II domain is conserved in all three SEL1L isoforms (10,16,17).…”

Section: Sel1l (Alias Sel1lmentioning

confidence: 99%

Functional Characterization of Two Secreted SEL1L Isoforms Capable of Exporting Unassembled Substrate

Cattaneo

Lotti

Martino

et al. 2009

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

SEL1L-A, a transmembrane glycoprotein residing in the endoplasmic reticulum (ER), is a component of the ER-associated degradation (ERAD) pathway. Alternative splicing generates two smaller SEL1L isoforms, -B and -C, that lack the SEL1L-A membrane-spanning region but retain some sel-1-like repeats, known to be involved in multi-protein interactions and signal transduction. In this study the functional characteristics of SEL1L-B and -C were investigated in human cell models. We show that these two isoforms are induced upon ER stress and activation of the unfolded protein response, together with SEL1L-A. Using transient transfection experiments (based on wild-type and mutant SEL1L constructs) combined with several biochemical tests we show that SEL1L-B and, more prominently, SEL1L-C are secreted glycoproteins. Although SEL1L-C is in monomeric form, SEL1L-B is engaged in intramolecular/intermolecular disulfide bonds. Both isoforms localize in secretory and degradative cellular compartments and in areas of cell-cell contact. However, whereas SEL1L-B is mainly associated with membranes, SEL1L-C shows the typical intralumenal localization of soluble proteins and is present in intercellular spaces. Furthermore, because of its peroxisomal domain, SEL1L-C localizes to peroxisomes. Both SEL1L-B and -C are involved in sorting and exporting unassembled Ig-s but do not affect two other ERAD substrates, the null Hong Kong variant of ␣ 1 -antitrypsin, and mutant ␣ 1 -AT Z. Overall these findings suggest that SEL1L-B and -C participate to novel molecular pathways that, in parallel with ERAD, contribute to the disposure of misfolded/unfolded or orphan proteins through degradation or secretion.

show abstract

Identification of a region within SEL1L protein required for tumour growth inhibition

Cited by 22 publications

References 17 publications

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

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

Multiprotein complexes that link dislocation, ubiquitination, and extraction of misfolded proteins from the endoplasmic reticulum membrane

Functional Characterization of Two Secreted SEL1L Isoforms Capable of Exporting Unassembled Substrate

Contact Info

Product

Resources

About