Structure, function, and expression of SEL-1, a negative regulator of LIN-12 and GLP-1 in C. elegans

Development ◽  
1997 ◽  
Vol 124 (3) ◽  
pp. 637-644 ◽  
Author(s):  
B. Grant ◽  
I. Greenwald
Keyword(s):  
Staining Pattern ◽  
Signal Sequence ◽  
Negative Regulator ◽  
Yeast Gene ◽  
Hydrophobic Region ◽  
C Elegans ◽  
Cell Ablation ◽  
New Information ◽  
Membrane Bound ◽  
Punctate Staining

Previous work indicated that sel-1 functions as a negative regulator of lin-12 activity, and predicted that SEL-1 is a secreted or membrane associated protein. In this study, we describe cell ablation experiments that suggest sel-1 mutations elevate lin-12 activity cell autonomously. We also use transgenic approaches to demonstrate that the predicted signal sequence of SEL-1 can direct secretion and is important for function, while a C-terminal hydrophobic region is not required for SEL-1 function. In addition, by analyzing SEL-1 localization using specific antisera we find that SEL-1 is localized intracellularly, with a punctate staining pattern suggestive of membrane bound vesicles. We incorporate these observations, and new information about a related yeast gene, into a proposal for a possible mechanism for SEL-1 function in LIN-12 turnover.

scholarly journals LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance

Oncogene ◽  
2021 ◽  
Author(s):  
Ola Billing ◽  
Ylva Holmgren ◽  
Daniel Nosek ◽  
Håkan Hedman ◽  
Oskar Hemmingsson
Keyword(s):  
Growth Factor Receptor ◽  
Braf Inhibitor ◽  
Treatment Resistance ◽  
Negative Regulator ◽  
C Elegans ◽  
Rtk Signaling ◽  
Egfr Expression ◽  
Inhibitor Resistance ◽  
Leucine Rich Repeats

AbstractLeucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-negative regulator of receptor tyrosine kinase (RTK) signaling and a tumor suppressor in several cancers, but its involvement in melanoma is largely unexplored. Here, we aim to determine the role of LRIG1 in melanoma tumorigenesis, RTK signaling, and BRAF inhibitor resistance. We find that LRIG1 is downregulated during early tumorigenesis and that LRIG1 affects activation of the epidermal growth factor receptor (EGFR) in melanoma cells. LRIG1-dependent regulation of EGFR signaling is evolutionary conserved to the roundworm C. elegans, where negative regulation of the EGFR-Ras-Raf pathway by sma-10/LRIG completely depends on presence of the receptor let-23/EGFR. In a cohort of metastatic melanoma patients, we observe an association between LRIG1 and survival in the triple wild-type subtype and in tumors with high EGFR expression. During in vitro development of BRAF inhibitor resistance, LRIG1 expression decreases; and mimics LRIG1 knockout cells for increased EGFR expression. Treating resistant cells with recombinant LRIG1 suppresses AKT activation and proliferation. Together, our results show that sma-10/LRIG is a conserved regulator of RTK signaling, add to our understanding of LRIG1 in melanoma and identifies recombinant LRIG1 as a potential therapeutic against BRAF inhibitor-resistant melanoma.

scholarly journals Control of Vulval Competence and Centering in the Nematode Oscheius sp. 1 CEW1

Genetics ◽  
2003 ◽  
Vol 163 (1) ◽  
pp. 133-146 ◽  
Author(s):  
Sophie Louvet-Vallée ◽  
Irina Kolotuev ◽  
Benjamin Podbilewicz ◽  
Marie-Anne Félix
Keyword(s):  
Germ Line ◽  
Specific Mechanism ◽  
C Elegans ◽  
Group 4 ◽  
Cell Ablation ◽  
Group 3 ◽  
Group 2 ◽  
P Cells ◽  
Large Category ◽  
Group 1

Abstract To compare vulva development mechanisms in the nematode Oscheius sp. 1 to those known in Caenorhabditis elegans, we performed a genetic screen for vulva mutants in Oscheius sp. 1 CEW1. Here we present one large category of mutations that we call cov, which affect the specification of the Pn.p ventral epidermal cells along the antero-posterior axis. The Pn.p cells are numbered from 1 to 12 from anterior to posterior. In wild-type Oscheius sp. 1 CEW1, the P(4-8).p cells are competent to form the vulva and the progeny of P(5-7).p actually form the vulva, with the descendants of P6.p adopting a central vulval fate. Among the 17 mutations (defining 13 genes) that we characterize here, group 1 mutations completely or partially abolish P(4-8).p competence, and this correlates with early fusion of the Pn.p cells to the epidermal syncytium. In this group, we found a putative null mutation in the lin-39 HOM-C homolog, the associated phenotype of which could be weakly mimicked by injection of a morpholino against Osp1-lin-39 in the mother’s germ line. Using cell ablation in a partially penetrant competence mutant, we show that vulval competence is partially controlled by a gonadal signal. Most other mutants found in the screen display phenotypes unknown in C. elegans. Group 2 mutants show a partial penetrance of Pn.p competence loss and an abnormal centering of the vulva on P5.p, suggesting that these two processes are coregulated by the same pathway in Oscheius sp. 1. Group 3 mutants display an enlarged competence group that includes P3.p, thus demonstrating the existence of a specific mechanism inhibiting P3.p competence. Group 4 mutants display an abnormal centering of the vulval pattern on P7.p and suggest that a specific mechanism centers the vulval pattern on a single Pn.p cell.

The Expression of Sel1L and Tan-1 in Normal and Neoplastic Cells

2000 ◽  
Vol 15 (1) ◽  
pp. 26-32 ◽  
Author(s):  
M. Cattaneo ◽  
R. Orlandi ◽  
C. Ronchini ◽  
P. Granelli ◽  
G. Malferrari ◽  
...  
Keyword(s):  
Cell Function ◽  
Sequence Similarity ◽  
Expression Patterns ◽  
Negative Regulator ◽  
Chromosomal Mapping ◽  
Normal Adult ◽  
Neoplastic Cells ◽  
C Elegans ◽  
Pancreatic Cancers ◽  
Almost All

We have previously reported on the isolation and chromosomal mapping of a novel human gene (SEL1L), which shows sequence similarity to sel-1, an extragenic suppressor of C. elegans. sel-1 functions as a negative regulator of lin-12 activity, the latter being implicated in the control of diverse cellular differentiation events. In the present study we compare the expression patterns of SEL1L and TAN-1, the human ortholog of lin-12 in normal and neoplastic cells. We found that, whereas both genes are expressed in fetal tissues at similar levels, they are differentially expressed in normal adult and neoplastic cells. In normal adult cells SEL1L is generally present at very low levels; only in the cells of the pancreas does it show maximum expression. By contrast, SEL1L is generally well represented in most neoplastic cells but not in those of pancreatic and gastric carcinomas, where transcription is either downregulated or completely repressed. TAN-1 on the other hand is well represented in almost all normal and neoplastic cells, with very few exceptions. Our observations suggest that SEL1L is presumably implicated in pancreatic and gastric carcinogenesis and that, along with TAN-1, it is very important for normal cell function. Alterations in the expression of SEL1L may be used as a prognostic marker for gastric and pancreatic cancers.

SRN1, a yeast gene involved in RNA processing, is identical to HEX2/REG1, a negative regulator in glucose repression

1992 ◽  
Vol 12 (6) ◽  
pp. 2673-2680
Author(s):  
K S Tung ◽  
L L Norbeck ◽  
S L Nolan ◽  
N S Atkinson ◽  
A K Hopper
Keyword(s):  
Rna Processing ◽  
Carbon Catabolite Repression ◽  
Glucose Repression ◽  
Complementation Group ◽  
Negative Regulator ◽  
Rrna Processing ◽  
Yeast Gene ◽  
Trna Splicing ◽  
Intervening Sequences ◽  
First Time

The yeast RNA1 gene encodes a cytosolic protein that affects pre-tRNA splicing, pre-rRNA processing, the production of mRNA, and the export of RNA from the nucleus to the cytosol. In an attempt to understand how the RNA1 protein affects such a diverse set of processes, we sought second-site suppressors of a mutation, rna1-1, of the RNA1 locus. Mutations in a single complementation group were obtained. These lesions proved to be in the same gene, SRN1, identified previously in a search for second-site suppressors of mutations that affect the removal of intervening sequences from pre-mRNAs. The SRN1 gene was mapped, cloned, and sequenced. DNA sequence analysis and the phenotype of disruption mutations showed that, surprisingly, SRN1 is identical to HEX2/REG1, a gene that negatively regulates glucose-repressible genes. Interestingly, SRN1 is not a negative regulator of RNA1 at the transcriptional, translational, or protein stability level. However, SRN1 does regulate the level of two newly discovered antigens, p43 and p70, one of which is not glucose repressible. These studies for the first time link RNA processing and carbon catabolite repression.

scholarly journals The purine nucleoside phosphorylase pnp-1 regulates epithelial cell resistance to infection in C. elegans

2021 ◽  
Author(s):  
Eillen Tecle ◽  
Crystal B. Chhan ◽  
Latisha Franklin ◽  
Ryan S. Underwood ◽  
Wendy Hanna-Rose ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Purine Nucleoside Phosphorylase ◽  
Negative Regulator ◽  
Purine Nucleoside ◽  
Intracellular Pathogens ◽  
Intestinal Epithelial ◽  
Purine Nucleotides ◽  
Nucleoside Phosphorylase ◽  
C Elegans ◽  
Pathogen Response

AbstractIntestinal epithelial cells are subject to attack by a diverse array of microbes, including intracellular as well as extracellular pathogens. While defense in epithelial cells can be triggered by pattern recognition receptor-mediated detection of microbe-associated molecular patterns, there is much to be learned about how they sense infection via perturbations of host physiology, which often occur during infection. A recently described host defense response in the nematode C. elegans called the Intracellular Pathogen Response (IPR) can be triggered by infection with diverse natural intracellular pathogens, as well as by perturbations to protein homeostasis. From a forward genetic screen, we identified the C. elegans ortholog of purine nucleoside phosphorylase pnp-1 as a negative regulator of IPR gene expression, as well as a negative regulator of genes induced by extracellular pathogens. Accordingly, pnp-1 mutants have resistance to both intracellular and extracellular pathogens. Metabolomics analysis indicates that C. elegans pnp-1 likely has enzymatic activity similar to its human ortholog, serving to convert purine nucleosides into free bases. Classic genetic studies have shown how mutations in human purine nucleoside phosphorylase cause immunodeficiency due to T-cell dysfunction. Here we show that C. elegans pnp-1 acts in intestinal epithelial cells to regulate defense. Altogether, these results indicate that perturbations in purine metabolism are likely monitored as a cue to promote defense against epithelial infection in the nematode C. elegans.Author summaryAll life requires purine nucleotides. However, obligate intracellular pathogens are incapable of generating their own purine nucleotides and thus have evolved strategies to steal these nucleotides from host cells in order to support their growth and replication. Using the small roundworm C. elegans, we show that infection with natural obligate intracellular pathogens is impaired by loss of pnp-1, the C. elegans ortholog of the vertebrate purine nucleoside phosphorylase (PNP), which is an enzyme involved in salvaging purines. Loss of pnp-1 leads to altered levels of purine nucleotide precursors and increased expression of Intracellular Pathogen Response genes, which are induced by viral and fungal intracellular pathogens of C. elegans. In addition, we find that loss of pnp-1 increases resistance to extracellular pathogen infection and increases expression of genes involved in extracellular pathogen defense. Interestingly, studies from 1975 found that mutations in human PNP impair T-cell immunity, whereas our findings here indicate C. elegans pnp-1 regulates intestinal epithelial immunity. Overall, our work indicates that host purine homeostasis regulates resistance to both intracellular and extracellular pathogen infection.

scholarly journals Identification of BMP and Activin Membrane-Bound Inhibitor (BAMBI) as a Potent Negative Regulator of Adipogenesis and Modulator of Autocrine/Paracrine Adipogenic Factors

Diabetes ◽  
2011 ◽  
Vol 61 (1) ◽  
pp. 124-136 ◽  
Author(s):  
X. Luo ◽  
L. J. Hutley ◽  
J. A. Webster ◽  
Y.-H. Kim ◽  
D.-F. Liu ◽  
...  
Keyword(s):  
Negative Regulator ◽  
Membrane Bound ◽  
Potent Negative Regulator

Developmental regulation of a novel repetitive protein of Trypanosoma brucei

1987 ◽  
Vol 7 (8) ◽  
pp. 2838-2844
Author(s):  
M R Mowatt ◽  
C E Clayton
Keyword(s):  
Trypanosoma Brucei ◽  
Tandem Repeats ◽  
Signal Sequence ◽  
Developmental Regulation ◽  
Developmentally Regulated ◽  
Hydrophobic Domain ◽  
Reading Frame ◽  
Amino Terminal ◽  
Membrane Bound

Trypanosoma brucei undergoes many morphological and biochemical changes during transformation from the bloodstream trypomastigote to the insect procyclic trypomastigote form. We cloned and determined the complete nucleotide sequence of a developmentally regulated cDNA. The corresponding mRNA was abundant in in vitro-cultivated procyclics but absent in bloodstream forms. The trypanosome genome contains eight genes homologous to this cDNA, arranged as four unlinked pairs of tandem repeats. The longest open reading frame of the cDNA predicts a protein of 15 kilodaltons, the central portion of which consists of 29 tandem glutamate-proline dipeptides. The repetitive region is preceded by an amino-terminal signal sequence and followed by a hydrophobic domain that could serve as a membrane anchor; the mRNA was found on membrane-bound polyribosomes. These results suggest that the protein is membrane associated.

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