Mitochondrial tumor suppressor 1
| Mitochondrial tumor suppressor 1 | ||
|---|---|---|
| Properties of human protein | ||
| Mass / length primary structure | 1270 amino acids | |
| Secondary to quaternary structure | Homodimer | |
| Cofactor | AGTR2, PTPN6 | |
| Isoforms | ATIP1, ATIP2, ATIP3a, ATIP3b, ATIP4, others | |
| Identifier | ||
| Gene name | MTUS1 | |
| External IDs | ||
| Occurrence | ||
| Parent taxon | Vertebrates | |
The Mitochondrial tumor suppressor 1 (MTUS1) is a protein in vertebrates , which in the regulation of cell cycle plays a role. The human gene was first described in 2003.
The protein interacts with the angiotensin II AT2 receptor, which supports the anti- proliferation of the respective cells and the inhibition of the ERK 2 activity of the classic MAP kinase pathway . It may also be involved in the intracellular transport of the AT2 receptor to act as a tumor suppressor gene .
Protein function
Almost simultaneously, three working groups isolated, amplified and sequenced the MTUS1 gene, which was given the different names MTSG, ATIP or ATBP depending on the function examined.
In 2003 a gene was isolated for the first time using the differential display method, which was clearly upregulated in non-proliferating and differentiated umbilical cord cells (HUVEC) in contrast to proliferating, undifferentiated cells. This gene was given the name mitochondrial tumor suppressor gene (MTSG1).
Furthermore, the recombinant expression of MTSG1 caused an inhibition of cell proliferation in a pancreatic tumor cell line. Based on the determined anti-proliferating effect and taking into account the location of the gene on chromosome 8 gene locus p21.3-22, which has a deletion in a large number of different tumor cells , the authors felt that MTSG1 is a tumor suppressor gene.
Two other research groups worked on the ability of the molecule to bind to the carboxy-terminal end of the angiotensin II AT2 receptor, which in turn should influence its expression and furthermore the signaling pathways of the receptor. Using the cDNA library from an adult human lung , a 1,977 nucleotide cDNA which encoded a 436 amino acid long polypeptide and also showed 100% homology to MTSG1 was identified. Due to the newly discovered functional property , the protein was named human AT2-interacting protein 1 (hATIP1). The associated mouse molecule with the abbreviated name “mATIP1”, which had 86% homology to “hATIP1”, was then isolated using the cDNA library of a fetal mouse . mATIP1 reduces the phosphorylation of the extracellular signal-related kinase 2 (ERK2), the classic MAP kinase pathway, if this was stimulated by insulin and the growth factors bFGF ( basic fibroblast growth factor ) and EGF ( epidermal growth factor ). Furthermore, the temporarily transfected mATIP1 inhibits the proliferation of CHO-AT2 clones and vascular muscle cells of the rat, if this was previously induced with fetal calf serum , EGF, PDGF ( platelet-derived growth factor ) and bFGF. These effects required the presence of the angiotensin II AT2 receptor and were only partially increased by the stimulation with angiotensin II .
Using the cDNA library from an 11 day old mouse embryo, an AT2 receptor binding protein weighing 50 kilodaltons was isolated and named ATBP50. ATBP50 is identical to mATIP1. However, the authors reported here that ATBP50 is required to express the AT2 receptor in an optimal way on the cell surface . As was also shown in ATBP50 knockdown experiments (transfection with short RNA complementary to ATBP50 mRNA), ATBP50 is also required for the inhibition of ERK2 activity and the antiproliferation mediated by the AT2 receptor.
Previous research has focused exclusively on ATIP1 or ATBP50, although the MTUS1 gene codes for a whole family of proteins in mice and humans. The human isoforms ATIP1, 3 and 4 and those of the mouse ATBP50, 135 and 60 are obtained through the alternative use of the promoter and / or the alternative splicing .
Regulation of activity
The inhibitory effect of ATIP1 or ATBP50 on ERK1 / 2 activity and cell proliferation seems to require the presence, but not the stimulation, of the AT2 receptor. However, stimulation with angiotensin II increases the effect.
Interactions with ligands and other proteins
ATIP and ATBP were treated with the yeast two-hybrid method, isolated, and used as bait ( bait ) served the C-terminal end of the AT2 receptor. Two working groups additionally confirmed by co-immunoprecipitation that ATIP1 and ATBP50 interact with the AT2 receptor. However, the AT2 receptor binding domain of the ATBP50 does not contain the last 30 amino acids of the C-terminal end, which was reported by Nouet et al. (2004) at ATIP1, as a 30 amino acid poly- proline sequence was described. According to Nouet et al. (2004) 118 amino acids from the extreme C-terminal end to the middle regions of ATIP1 belong to the interacting domain.
The other isoforms ATBP60 and ATBP135 do not seem to bind to the AT2 receptor.
In addition to the binding to the AT2 receptor, the possibilities for homo- and heterodimerization were described for the isoforms of ATIP and ATBP.
Regulation of concentration
The expression of MTUS1 or ATBP seems to be dependent on the co-expression with the AT2 receptor, since in AT2 receptor-deficient mice the ATBP mRNA expression was reduced to up to 10% of the normal expression (Wruck et al. 2005). Furthermore, by stimulating the AT2 receptor with angiotensin II, the expression of the ATBP could be increased.
Originally described as a tumor necrosis factor suppressor gene, the expression of MTUS1 in tumor cells was greatly reduced compared with control tissue . To date, these observations have been confirmed in a pancreatic carcinoma and an ovarian carcinoma .
Subcellular localization
The subcellular localization of the molecule is still largely unclear. It could be cell type-specific or it could change depending on the particular interaction partner. MTSG1 has been described as being primarily localized to the mitochondrion . In addition, the existence of an N-terminal mitochondrial target sequence was postulated. ATBP, in turn, is said to interact with the Golgi apparatus through a C-terminal domain. This observation is supported by the homologies of the ATBP with Golgi -binding “Hook” proteins.
Splice variants
Some isoforms for ATIP and ATBP are described. ATIP was isolated from human (hATIP1) and mouse tissue. Northern blot analyzes with a 3 'ATIP probe revealed three large mRNA transcripts that were at heights of 6.9; 4.2 and 1.8 kilobases migrated. At the protein level , four large polypeptides were detected by Western blot analyzes using antibodies directed against the AT2 receptor-binding domain of the ATIP. These polypeptides had molecular weights of 30, 60, 120 and 180 kilodaltons. These could represent different isoforms of the hATIP or reflect the presence of post-translational modifications or the presence of ATIP dimers .
Individual evidence
- ↑ Homologues at OMA
- ↑ a b c d e S. Seibold et al: Identification of a new tumor suppressor gene located at chromosome 8p21.3-22. In: FASEB J 17, 2003, pp. 1180-1182. PMID 12692079
- ↑ a b c d e f g h S. Nouet et al .: Trans-inactivation of receptor tyrosine kinases by novel angiotensin II AT2 receptor-interacting protein, ATIP. In: J Biol Chem 279, 2004, pp. 28989-28997. PMID 15123706
- ↑ a b c d e f g h i C. J. Wruck et al: Regulation of transport of the angiotensin AT2 receptor by a novel membrane-associated Golgi protein. In: Arterioscler Thromb Vasc Biol 15, 2005, pp. 539-617. PMID 15539617
- ↑ P. Horak et al .: Perturbation of the tumor necrosis factor - related apoptosis-inducing ligand cascade in ovarian cancer: overexpression of FLIPL and deregulation of the functional receptors DR4 and DR5. In: Clin Cancer Res 11, 2005, pp. 8585-8591. PMID 16361541
literature
- M. Di Benedetto et al .: Mutation analysis of the 8p22 candidate tumor suppressor gene ATIP / MTUS1 in hepatocellular carcinoma. In: Mol Cell Endocrinol 252, 2006, pp. 207-215. PMID 16650523
- B. Frank et al .: Copy number variant in the candidate tumor suppressor gene MTUS1 and familial breast cancer risk. In: Carcinogenesis , 28, 2007, pp. 1442-1445. PMID 17301065
- M. Di Benedetto ua: Structural organization and expression of human MTUS1, a candidate 8p22 tumor suppressor gene encoding a family of angiotensin II AT2 receptor-interacting proteins, ATIP. In: Gene 380, 2006, pp. 127-136. PMID 16887298
- JF Rual et al .: Towards a proteome-scale map of the human protein-protein interaction network. In: Nature 437, 2005, pp. 1173-1178. PMID 16189514
- T. Ota et al .: Complete sequencing and characterization of 21,243 full-length human cDNAs. In: Nature Genetics 36, 2004, pp. 40-45. PMID 14702039
- RL Strausberg et al .: Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. In: PNAS 99, 2003, pp. 16899-16903. PMID 12477932
- T. Nagase et al .: Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. In: DNA Res 6, 2000, pp. 337-345. PMID 10574462