|CSC-DC001236||Panoply™ Human AVEN Knockdown Stable Cell Line||Inquiry|
|CSC-SC001236||Panoply™ Human AVEN Over-expressing Stable Cell Line||Inquiry|
|CDCB161666||Chicken AVEN ORF Clone (NM_001005791)||Inquiry|
|CDCB171644||Danio rerio AVEN ORF Clone (NM_001045292)||Inquiry|
|CDCB185201||Rabbit AVEN ORF clone (XM_008269583.1)||Inquiry|
|CDCR032472||Mouse Aven ORF clone (NM_001165935.1)||Inquiry|
|CDCR261950||Mouse Aven ORF Clone(NM_028844.3)||Inquiry|
|CDCR305264||Human AVEN ORF Clone(NM_020371.2)||Inquiry|
|CDCR374303||Rat Aven ORF Clone(NM_001107757.1)||Inquiry|
|CDFG002644||Human AVEN cDNA Clone(NM_020371.2)||Inquiry|
|CDFG002645||Human AVEN cDNA Clone(NM_020371.2)||Inquiry|
|CDFG020754||Mouse Aven cDNA Clone(NM_001165935.1)||Inquiry|
|CDFL001671||Mouse Aven cDNA Clone(NM_028844.3)||Inquiry|
|CDFR007397||Rat Aven cDNA Clone(NM_001107757.1)||Inquiry|
|MiUTR1H-00750||AVEN miRNA 3'UTR clone||Inquiry|
|SHG086599||shRNA set against Human AVEN(NM_020371.2)||Inquiry|
|SHH243790||shRNA set against Mouse AVEN (NM_028844.3)||Inquiry|
|SHH243794||shRNA set against Rat AVEN (NM_001107757.1)||Inquiry|
|SHW000191||shRNA set against Chicken AVEN (NM_001005791)||Inquiry|
|SHW010169||shRNA set against Danio rerio AVEN (NM_001045292)||Inquiry|
Apoptosis caspase activation inhibitor (AVEN) is an apoptosis-suppressing gene selected by the two-hybrid method of the copper drum yeast. AVEN inhibits the hydrolysis of apoptotic protease by interfering with the self-crosslinking ability of apoptosis activating, factor-1, (apaf-1), thereby exerting the anti-apoptotic effect. In addition, AVEN also interacts with the N-terminal region and BH1 domain of Bcl-xL, a member of the BCL-2 anti-apoptotic family, which enhances the anti-apoptotic function of Bcl-xL.
Han et al. showed that the protein level of AVEN is regulated by the Akt signaling pathway. In this process, AVEN is primarily regulated by the activity of cathepsin D, increasing the sensitivity of cancer cells to chemotherapeutic agents. Various studies have shown that the anti-apoptotic protein AVEN has potential carcinogenic effects. However, the molecular mechanism of AVEN expression remains to be elucidated.
AVEN Structure and Function
AVEN can disrupt the oligomerization of Apaf-1, leading to inactivation of caspase-9 and inhibition of apoptosis. Furthermore, AVEN has been reported to be cleaved by the aspartic protease cathepsin D at the L144/196 site and the C-terminal ΔN-AVEN produced by this cleavage is essential for its anti-apoptotic function. In addition to its anti-apoptotic function, AVEN also plays an important role in responding to DNA damage. After DNA damage, AVEN is activated by cataxia-telangiectasia mutated (ATM) to promote cell cycle inhibition, ATM protein kinase activation and phosphorylation of the cell cycle. AVEN can act as an ATM catalyst to inhibit G2/M progression. Activated ATM phosphorylates AVEN on S135/308 and induces complete activation of AVEN. Activated AVEN then further enhances ATM activation, resulting in activation of downstream pathway components to inhibit Cdc25 activation and enhance Wee1/Myt kinase activity. This leads to subsequent inhibition of mitotic entry.
AVEN binds its RNA to the G4 structure via its RGG / RG motif. AVEN's RGG/RG motif is composed of PRMT1 methylated arginine, thus promoting binding to the methylarginine interactors SMN and TDRD3, which is required for AVEN to bind to polysomes. Moreover, AVEN recruits DHX36 to polysomes, which may help unravel the G4 structure during translation. Consumption of AVEN / DHX36 inhibits KMT2A / KMT2B translation, whereas luciferase assays using G-to-A mutagenesis indicate that both AVEN and DHX36 need to rescue translation in the presence of the G4 motif. Therefore, RNA G4 binding proteins can play a key role in regulating AVEN mRNA translation.
Figure 1. Methylated AVEN binds G4 structures in the ORFs of MLL1 and MLL4 mRNAs in an RGG/RG motif (denoted as vv) dependent manner. (Song, et al, 2016)
AVEN and Acute Leukemia
Studies have shown that the protein level of AVEN is increased in acute leukemia. AVEN overexpression is associated with poor prognosis in childhood acute lymphoblastic leukemia and may be a novel prognostic indicator for this malignancy. A study investigated 37 acute myeloblastic leukemia (AML) and 28 acute lymphoblastic leukemia (ALL) and found that the level of AVEN in leukemia patients was higher than in healthy people. Moreover，The level of AVEN will be higher in people with the relapsed disease compared with those without recurrence disease. This suggests that AVEN is an important anti-apoptotic signal for acute leukemia.
In addition, a study investigated the results of AVEN expression and treatment in 91 patients with acute lymphoblastic leukemia. The results showed that AVEN was highly expressed in patients. In the standard relapse group, the expression level of AVEN also increased significantly. Therefore, overexpression of AVEN is an independent poor prognostic factor and can be used to predict the prognosis of childhood disease.
AVEN and Breast Cancer
The formation of breast cancer is the result of the imbalance of tumor cell proliferation and apoptosis, which is closely related to DNA damage. AVEN is a key sensor for DNA damage. Analysis of breast cancer tissue microarrays showed a decrease in AVEN expression in breast cancer tissues compared to non-neoplastic breast tissue. In particular, the expression of AVEN in invasive ductal carcinoma and papillary carcinoma breast cancer subtypes was decreased compared to non-tumorous breast tissue and invasive lobular breast cancer tissue. Studies have shown that AVEN is an important mediator of DNA damage-induced apoptosis signaling in breast cancer cells, and its nuclear expression changes in breast cancer tissues, which may lead to genomic instability of breast cancer tumors.
Ouzounova et al. showed that AVEN is a downstream target gene for reverse transcriptional regulation of the miR-30 family. This is very important for the regulation of breast cancer cells in non-adherent conditions. Overexpression of MiR30 family members reduces breast tumor progression and tumor ball formation as well as AVEN expression.
Studies have shown that AVEN's forced expression blocks UV-radio, SN-38 or cisplatin-induced apoptosis in upstream mitochondria by stabilizing Bcl-xL protein levels in breast cancer cells. AVEN silencing by RNA interference significantly enhanced the apoptotic response following treatment with DNA damaging agents. AVEN complexes with Bcl-xL in untreated breast cancer cells and treatment with DNA damaging agents results in a decrease in AVEN/Bcl-xL interaction. Importantly, Bcl-xL is essential for the survival activity of AVEN, and the depletion of Bcl-xL abolishes AVEN-mediated protection against DNA damage-induced apoptosis.
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