The Apaf-1-binding protein Aven is cleaved by Cathepsin D to unleash its anti-apoptotic potential

Abstract

The anti-apoptotic molecule Aven was originally identified in a yeast two-hybrid screen for Bcl-x L -interacting proteins and has also been found to bind Apaf-1, thereby interfering with Apaf-1 self-association during apoptosome assembly. Aven is expressed in a wide variety of adult tissues and cell lines, and there is increasing evidence that its overexpression correlates with tumorigenesis, particularly in acute leukemias. The mechanism by which the anti-apoptotic activity of Aven is regulated remains poorly understood. Here we shed light on this issue by demonstrating that proteolytic removal of an inhibitory N-terminal Aven domain is necessary to activate the anti-apoptotic potential of the molecule. Furthermore, we identify Cathepsin D (CathD) as the protease responsible for Aven cleavage. On the basis of our results, we propose a model of Aven activation by which its N-terminal inhibitory domain is removed by CathD-mediated proteolysis, thereby unleashing its cytoprotective function.

MicroRNA miR-30 family regulates non-attachment growth of breast cancer cells

“…Although Ubc9 and ITGB3 were not included in our final list of miR-30a targets, we studied in more detail other targets also potentially involved in apoptosis and proliferation. FOXD1 (forkhead box protein 1) has a role in tumor formation [28], while AVEN (apoptosis, caspase activation inhibitor) has an established role in apoptosis regulation [21,24]. Although AVEN is unlikely to be the only miR-30a target involved in non-attachment growth, our results suggest an important role in this process that should be followed in further studies.…”

“…However, we were interested in investigating in more detail the role of AVEN, because of the link between increased expression of this protein and cell survival [21], and poor prognosis in different types of human malignancies [22,23]. Moreover, the role of AVEN has been specifically addressed in breast cancer cells, including MCF7 cells [24]. We used endoribonuclease-prepared siRNA pools (esiRNA) targeting AVEN coding sequence to transiently silence AVEN expression in MCF7 cells.…”

Progesterone Regulation of AVEN Protects Bovine Oocytes from Apoptosis During Meiotic Maturation1

“…Several known regulatory domains were found to be conserved in the bovine sequence, including the Bcl-x L binding domain [21], the Cathepsin D cleavage site [31] and Caspase 8/9 cleave domain [32]. The AVEN protein sequence was also found to contain several conserved putative phosphomotifs, including a CK2 motif, an ATM motif and a Protein Kinase A (PKA) motif.…”

“…The AVEN protein is known to contain a BCL-x L binding site [21], multiple ATM phosphorylation sites [20] and Cathepsin D and Caspase 8/9 cleavage sites [31,32]. In addition, the AVEN protein contains several conserved putative phosphomotifs, including an additional CK2 motif, an additional ATM motif and a Protein Kinase A (PKA) motif (illustrated in Figure 1), all of which are known regulators of the cell cycle and/or oocyte maturation and may function during oocyte maturation in cattle.…”

5-Aza-2’-deoxycytidine may influence the proliferation and apoptosis of cervical cancer cells via demethylation in a dose- and time-dependent manner

“…In our study, 5-Aza-CdR-treated HeLa cells showed a higher apoptosis rate than untreated HeLa cells. The expression of APAF-1 is correlated with cancer cell apoptosis (Andreev et al, 2012;Niimi et al, 2012;Melzer et al, 2012). Presumably, 5-Aza-CdR reduces APAF-1 methylation and restores its expression, thus reactivating its functions.…”