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| | AVEN protein: 1-362 aa. Cathepsin D cleavage sites: L144 and L196; putative BH3 domain: aa141-153; NES: aa282-293. ATM kinase phosphorylation sites: S 135 and S 308. |
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| Description | The AVEN protein possesses no predicted domains according to the NCBI database. However, a sequential proteolytic processing of AVEN by the lysosomal protease cathepsin D has been published (Melzer et al., 2012), leading to the cleavage of AVEN at aa 144 and 196 and the generation of a shorter isoform (deltaN Aven) that is supposed to be associated with the antiapoptotic function. Moreover, AVEN is able to bind to the DNA damage response regulating kinase ATM (ataxia telangiectasia mutated) and is phosphorylated by ATM at S135 and S308 (Guo et al., 2008). In addition, a potential nuclear export sequence (NES) to exists between aa 282-293 (Esmaili et al., 2010) and a putative BH3 motif (for binding to Bcl-xL) has been predicted to be located between aa 141-153 (Hawley et al., 2012). |
| Expression | Widely expressed throughout the human organism (Chau et al., 2000). |
| Localisation | Mostly cytosolic, punctuate, reticular pattern (associated with intracellular membrane localization, lysosomal?) in the cytosol (Chau et al., 2000), diffuse nuclear staining (Esmaili et al., 2010). |
| Function | Antiapoptotic:
AVEN was first discovered as an interactor of the antiapoptotic BCl-xL protein by Chau et al. (2000). It was also shown to bind to the proapoptotic APAF-1 protein and postulated to prevent the oligomerization of APAF-1 (apoptosome formation) in the intrinsic apoptosis pathway and to stabilize the Bcl-xL protein by binding to it (Kutuk et al., 2010). Putative binding sites in Bcl-xL are predicted to be located in the Bcl-xL BH1 and BH4 domains (Hawley et al., 2012). Recently, it was shown that AVEN can be processed by the lysosomal protease Cathepsin D at aa 144 and 196, and that this processing is neccessary to activate AVEN's antiapoptotic function (Melzer et al., 2012). It is still unclear whether it is the stabilization of Bcl-xL, the interference with apoptosome assembly or another feature of AVEN that is responsible for the antiapoptotic capacity of this protein. DNA damage repair:
It was shown by Guo et al. (2008) that AVEN, in addition to binding to the apoptotic machinery, is also able to bind one of the key players in DNA damage repair, the ataxia telangiectasia mutated (ATM) kinase. Overexpression of AVEN in Xenopus laevis egg extracts induced a cell cycle arrest at G2/M which is in large part ATM dependent, whereas the absence of AVEN impaired ATM-mediated checkpoint function. An intrinsic loop of activation exists between AVEN and ATM: AVEN binds to the kinase domain of ATM (appr. aa 2500-3000) and, in turn, is phosphorylated by ATM at S135 and S308. This phosphorylation seems to enhance AVEN's activating influence on ATM. Esmaili et al. (2010) were able to demonstrate that AVEN possesses a nuclear export signal (NES) which is located between aa 282 and 293. Under normal physiological conditions, AVEN is shuttled outside of the nucleus by Exportin-1/CRM1 whereas inhibition of CRM1 by leptomycin or mutation of the AVEN NES leads to nuclear accumulation of the protein. The NES/nuclear-cytosolic shuttling of AVEN might be important for its cell cycle regulatory functions and its role in DNA damage repair.
Depending on the degree of DNA damage, AVEN is possibly a multifunctional protein, finetuning the cellular decisions of cell cycle arrest and apoptosis in the DNA damage response. |
| Homology | No close orthologs of AVEN in humans are known. However, Hawley et al. (2010) note homology to Bik (58% homology over a 77 aa region encompassing the putative BH3 homology domain).
Homologs of AVEN can be found in several species, like mouse (NCBI acc. Nr. NP_083120), Drosophila (NP_572817), rat (NP_001101227), chicken (NP_001005791; Vezyri et al., 2011) and Xenopus (NP_001090621; Guo et al., 2008). Of note, two isoforms are postulated to exist in mouse, the second one (NP_001159407) possessing a distinctly shorter N-terminus than the full length protein. However, nothing is known about the function or biological relevance of this predicted second isoform. Functional similarity to the human protein in its cell cycle regulatory properties has been published for the Drosophila (Zou et al., 2011) and the Xenopus homologs (Guo et al., 2008). |
| Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1. |
| Chau BN, Cheng EH, Kerr DA, Hardwick JM. |
| Mol Cell. 2000 Jul;6(1):31-40. |
| PMID 10949025 |
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| Aven overexpression: association with poor prognosis in childhood acute lymphoblastic leukemia. |
| Choi J, Hwang YK, Sung KW, Kim DH, Yoo KH, Jung HL, Koo HH. |
| Leuk Res. 2006 Aug;30(8):1019-25. Epub 2006 Jan 18. |
| PMID 16388850 |
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| Overexpression of the anti-apoptotic protein AVEN contributes to increased malignancy in hematopoietic neoplasms. |
| Eissmann M, Melzer IM, Fernandez SB, Michel G, Hrabe de Angelis M, Hoefler G, Finkenwirth P, Jauch A, Schoell B, Grez M, Schmidt M, Bartholomae CC, Newrzela S, Haetscher N, Rieger MA, Zachskorn C, Mittelbronn M, Zornig M. |
| Oncogene. 2013 May 16;32(20):2586-91. doi: 10.1038/onc.2012.263. Epub 2012 Jul 2. |
| PMID 22751129 |
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| Regulation of the ATM-activator protein Aven by CRM1-dependent nuclear export. |
| Esmaili AM, Johnson EL, Thaivalappil SS, Kuhn HM, Kornbluth S, Irusta PM. |
| Cell Cycle. 2010 Oct 1;9(19):3913-20. Epub 2010 Oct 25. |
| PMID 20935510 |
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| Aven-dependent activation of ATM following DNA damage. |
| Guo JY, Yamada A, Kajino T, Wu JQ, Tang W, Freel CD, Feng J, Chau BN, Wang MZ, Margolis SS, Yoo HY, Wang XF, Dunphy WG, Irusta PM, Hardwick JM, Kornbluth S. |
| Curr Biol. 2008 Jul 8;18(13):933-42. doi: 10.1016/j.cub.2008.05.045. Epub 2008 Jun 19. |
| PMID 18571408 |
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| An Integrated Bioinformatics and Computational Biology Approach Identifies New BH3-Only Protein Candidates. |
| Hawley RG, Chen Y, Riz I, Zeng C. |
| Open Biol J. 2012 May 4;5:6-16. |
| PMID 22754595 |
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| Aven blocks DNA damage-induced apoptosis by stabilising Bcl-xL. |
| Kutuk O, Temel SG, Tolunay S, Basaga H. |
| Eur J Cancer. 2010 Sep;46(13):2494-505. doi: 10.1016/j.ejca.2010.06.011. Epub 2010 Jul 7. |
| PMID 20619636 |
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| The Apaf-1-binding protein Aven is cleaved by Cathepsin D to unleash its anti-apoptotic potential. |
| Melzer IM, Fernandez SB, Bosser S, Lohrig K, Lewandrowski U, Wolters D, Kehrloesser S, Brezniceanu ML, Theos AC, Irusta PM, Impens F, Gevaert K, Zornig M. |
| Cell Death Differ. 2012 Sep;19(9):1435-45. doi: 10.1038/cdd.2012.17. Epub 2012 Mar 2. |
| PMID 22388353 |
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| MicroRNA miR-30 family regulates non-attachment growth of breast cancer cells. |
| Ouzounova M, Vuong T, Ancey PB, Ferrand M, Durand G, Le-Calvez Kelm F, Croce C, Matar C, Herceg Z, Hernandez-Vargas H. |
| BMC Genomics. 2013 Feb 28;14:139. doi: 10.1186/1471-2164-14-139. |
| PMID 23445407 |
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| Survivin and aven: two distinct antiapoptotic signals in acute leukemias. |
| Paydas S, Tanriverdi K, Yavuz S, Disel U, Sahin B, Burgut R. |
| Ann Oncol. 2003 Jul;14(7):1045-50. |
| PMID 12853345 |
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| Molecular cloning and expression of Aven gene in chicken. |
| Vezyri E, Mikrou A, Athanassiadou A, Zarkadis IK. |
| Protein J. 2011 Jan;30(1):72-6. doi: 10.1007/s10930-011-9304-6. |
| PMID 21234663 |
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| Identification of dAven, a Drosophila melanogaster ortholog of the cell cycle regulator Aven. |
| Zou S, Chang J, LaFever L, Tang W, Johnson EL, Hu J, Wilk R, Krause HM, Drummond-Barbosa D, Irusta PM. |
| Cell Cycle. 2011 Mar 15;10(6):989-98. Epub 2011 Mar 15. |
| PMID 21368576 |
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