A novel early estrogen-regulated gene gec1 encodes a protein related to GABARAP

ArticleinBiochemical and Biophysical Research Communications 284(1):118-25 · July 2001with8 Reads
DOI: 10.1006/bbrc.2001.4908 · Source: PubMed
Abstract
We have isolated, in guinea-pig endometrial cells, an estrogen-induced 1.8 kb RNA called gec1. Screening of a guinea-pig genomic library led to identification of gec1 gene consisting of 4 exons and 3 introns. Exon 1 contains the 5'UTR and the ATG initiation codon. A guinea-pig gec1 cDNA was obtained by 5'-RACE. The 351 bp coding sequence shares 76.8% identity with that of the human GABARAP 924 bp cDNA while UTRs of the two cDNAs differ. A gec1 probe from the 3'UTR revealed a 1.9 kb mRNA in human tissues and a human GEC1 cDNA was isolated from placenta. Its coding sequence shares 93 and 79% identity with that of guinea-pig gec1 and human GABARAP, respectively. The human and guinea-pig GEC1 proteins have 100% identity. GEC1 and GABARAP proteins have 87% identity and N terminus featuring a tubulin binding motif. Thus, estrogen-regulated gec1 is a new gene which could encode a microtubule-associated protein.
    • "GABARAPL1 may, therefore, play a protective role in this disease by aiding in the degradation of unwanted α-synuclein aggregates until such time as it is downregulated with the progression of the disease. Indeed, gabarapl1 transcription is upregulated in the presence of estrogens [42] and estrogen has been show to have a protective effect on an MPTP murine model of Parkinson's disease [43]. "
    [Show abstract] [Hide abstract] ABSTRACT: Macroautophagy is a highly conserved cellular degradation process, regulated by autophagy-related (atg) factors, in which a double membrane autophagosome engulfs cytoplasmic components to target them for degradation. In yeast, the Atg8 protein is indispensable for autophagosome formation. In mammals, this is complicated by the presence of six Atg8 homologues grouped into the GABARAP and MAP1LC3 subfamilies. Although these proteins share a high similarity, their transcript expression, regulation and protein interactions differ, suggesting they may display individual properties and specific functions. GABARAPL1/GEC1 is a member of the GABARAP subfamily and its mRNA is the most highly expressed Atg8 homologue in the central nervous system. Consequently, we performed an in depth study of GABARAPL1 distribution in the developing and adult murine brain. Our results show that GABARAPL1 brain expression is visible as early as embryonic day 11 and progressively increases to a maximum level in the adult. Immunohistochemical staining was detected in both fibers and immature neurons in embryos but was restrained to neurons in adult tissue. By E17, intense punctate-like structures were visible and these accumulated in cortical primary neurons treated with the autophagosome/lysosome fusion inhibitor Bafilomycin A1 (Baf A1), suggesting that they represent autophagosomes. Finally, GABARAPL1 expression was particularly intense in motoneurons in the embryo and in neurons involved in somatomotor and neuroendocrine functions in the adult, particularly in the substantia nigra pars compacta, a region affected in Parkinson's disease. Our study of cerebral GABARAPL1 protein expression provides insight into its role in the development and homeostasis of the mouse brain.
    Full-text · Article · May 2013
    • "GABARAP has also been characterized as a mammalian homolog of the yeast Atg8 (autophagy-related protein8)/Apg8/ Aut7; other homologues include LC3 (microtubule-associated protein 1 light chain 3), Golgi-associated ATPase enhancer of 16 kDa (GATE-16)/GABARAPL2/GEF2, and Atg8L [10,11]. GABARAP is also highly homologous with the other Atg8 homologs, especially with Atg8L/GEC1/GABARAPL1 (87% identity and 97% similarity) and GATE-16 (57% identity and 97% similarity) [4,12,13,14,15,16] . We have shown that GA- BARAP, along with the other Atg8 homologs, can act as a ubiquitin-like modifier protein, and that GABARAP modification is mediated by the cysteine protease Atg4B, the E1-like enzyme Atg7/Apg7, and the E2-like enzyme Atg3/Apg3 [10,11,17,18,19,20]. "
    [Show abstract] [Hide abstract] ABSTRACT: GABAA receptor-associated protein (GABARAP) was initially identified as a protein that interacts with GABAA receptor. Although LC3 (microtubule-associated protein 1 light chain 3), a GABARAP homolog, has been localized in the dendrites and cell bodies of neurons under normal conditions, the subcellular distribution of GABARAP in neurons remains unclear. Subcellular fractionation indicated that endogenous GABARAP was localized to the microsome-enriched and synaptic vesicle-enriched fractions of mouse brain as GABARAP-I, an unlipidated form. To investigate the distribution of GABARAP in neurons, we generated GFP-GABARAP transgenic mice. Immunohistochemistry in these transgenic mice showed that positive signals for GFP-GABARAP were widely distributed in neurons in various brain regions, including the hippocampus and cerebellum. Interestingly, intense diffuse and/or fibrillary expression of GFP-GABARAP was detected along the axonal initial segments (AIS) of hippocampal pyramidal neurons and cerebellar Purkinje cells, in addition to the cell bodies and dendrites of these neurons. In contrast, only slight amounts of LC3 were detected along the AIS of these neurons, while diffuse and/or fibrillary staining for LC3 was mainly detected in their cell bodies and dendrites. These results indicated that, compared with LC3, GABARAP is enriched in the AIS, in addition to the cell bodies and dendrites, of these hippocampal pyramidal neurons and cerebellar Purkinje cells.
    Full-text · Article · May 2013
    • "To reveal the role of DEP domain in Wnt signaling, a yeast two-hybrid assay was performed using DEP domain and C-terminal of Dvl2 as bait to screen an 11.5-day mouse embryo cDNA library in this study. We have obtained a clone coding GABARAPL1 (GABA A receptor-associated protein like 1) protein [16]. GABARAPL1 belongs to the GABARAP protein family which contains 6 members in mammalian cells, including MAP1LC3A (microtubule-associated proteins-1 light chain 3A), MAP1LC3B, MAP1LC3C, GABARAP and GABARAPL2/GATE16 [17]. "
    [Show abstract] [Hide abstract] ABSTRACT: Wnt signaling is critical for many biological processes and is tightly regulated. In this study, we found that GABARAPL1 (GABA(A) receptor-associated protein like 1, GABARAPL1) interacts with Dvl2 by both yeast two-hybrid screening and immunoprecipitation experiments. Furthermore, we observed that p62 is required for the interaction of Dvl2 and GABARAPL1. Luciferase assays indicated that GABARAPL1 represses Wnt/β-catenin signaling stimulated by Wnt1, Dvl2 and β-catenin. We further demonstrated that GABARAPL1 mediates degradation of Dvl2 and the effect is blocked by addition of 3-MA, a specific inhibitor of autophagy. Finally, we provided evidence that over-expression of GABARAPL1 inhibits proliferation and tumor growth of MCF7 cells in vitro and in nude mice. Taken together, our results suggested that GABARAPL1 as a tumor repressor inhibits Wnt signaling via mediating Dvl2 degradation through the autophagy pathway.
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