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ATPase family AAA domain-containing protein 2 (ATAD2) is a member of the ATPase family. ATAD2 gene expression has specificity in tissue, cell distribution, and developmental stages. They are widely involved in physiological and pathological processes such as cell proliferation, differentiation, apoptosis and tumorigenesis, and development.
The ATAD2-encoded protein has two domains: the AAA region and the bromine region domain. AAA+ proteins are composed of evolutionarily conserved enzymes. The AAA region acts as a molecular chaperone to perform the functions of assembling, manipulating, and decomposing protein complexes. The bromodomain is an evolutionarily highly conserved protein functional domain consisting of 60-110 amino acids that specifically recognizes the acetylated lysine site of histones. It is also involved in signal-dependent gene transcriptional regulation through chromatin assembly and acetylation. It can also be widely involved in cell cycle regulation, signal transduction and other processes through acetylation modification of non-histone proteins such as transcription factors.
ATAD2 Gene Expression Regulation Function
ATAD2 is a cofactor for c-MYC, androgen receptor (AR) and ER-a, regulated by androgens and estrogens and E2Fs (E2F1 to E2F3). At the transcriptional and protein translational levels, high expression of ATAD2 regulates key gene expression in cell proliferation, such as cyclinA2, cyclin E1, cdk2, cdc6, and MCM7. It also involves gene expression of cell cycle progression and DNA synthesis replication, such as cyclinB1, cdc2, PCNA, RFC2, MCM2, geminin, and PROM2. A recent study by Zou et al. showed that ATAD2 forms a co-expression complex with c-MYC, controls a specific androgen subgroup and induces gene proliferation and survival, and participates in tumor development. ATAD2 promotes cell proliferation by controlling B-Myb and EZH2 in breast cancer. In prostate cancer cells, ATAD2 is a coactivator of androgen receptor and MYC protein. The gene expression of ATAD2 is regulated by androgen by AR binding sequence (ARBS), which is a distal enhancer present in the regulatory region of ATAD2.
ATAD2 and Tumor
Wu et al. found that in some tumors involved in the regulation of chromatin dynamic activity, genomic transcriptional activity and apoptosis process, can promote the proliferation of tumor cells and inhibit their differentiation. Hwang found that ATAD2 mRNA and protein expression levels were higher in human hepatocarcinoma tissues than in paracancerous liver tissues, and the expression level of ATAD2 was found to be closely related to tumor metastasis and prognosis. Lu et al. can significantly inhibit the invasion and metastasis of hepatocarcinoma cells by inhibiting the expression of ATAD2, indicating that the abnormal expression of ATAD2 may be involved in the development of liver cancer.
Figure 1. Schematic model of ATAD2 interaction with MKK3/6 and subsequent regulation of p38 phosphorylation-mediated apoptosis. (Lu, W. J., et al. 2015)
Compared with the low expression of ATAD2 in mature prostate tissue, ATAD2 was highly expressed in both early prostate tissue and prostate cancer tissues. E18 embryos to 12-month-old mouse prostate tissue were immunohistochemical staining by Raeder et al., which showed that that ATAD2 was strongly expressed in both mouse and human urogenital epithelial and mesenchymal tissues. However, when castrated or passed testosterone, the expression of ATAD2 is strongly inhibited in both normal tissues and tumor tissues. It was demonstrated that ATAD2 is regulated by androgen.
The study group also showed that high expression of ATAD2 may be the deregulation of the pRB pathway. ATAD2 mRNA levels are regulated by the loss of the Rb-1 gene and the expression of the E1A oncoprotein. The MYC oncogene is located at the end of the chromosome 8q24, 4, 3Mb centromeres, and the endogenous or ectopic interaction between ATAD2 and MYC in vivo depends on the NH2 terminus of ATAD2. ATAD2 may be part of a transcriptionally activated MYC complex.
Overexpression of ATAD2 in breast cancer and its protein level is closely related to pathological staging and histological grade. In particular, it is significantly associated with triple-negative breast cancer (both estrogen receptor, progesterone receptor, and human epidermal growth factor receptor are negative) and is associated with tumor metastasis. Therefore, in breast cancer, ATAD2 can be used as a prognostic indicator and a new target for targeted therapy of triple-negative breast cancer.
Studies have shown that ATAD2 is a target gene for E2F in breast cancer and binds to MYC oncogenes. High ATAD2 levels are associated with a high risk of long-term recurrence of breast cancer and survival. Mutation of the ATAD2 bromodomain disrupts the binding of ATAD2 to histone H3. Knockout of ATAD2 gene expression inhibited estrogen-mediated induction of cyclin D1, c-MYC, and E2F1 mRNA. The mutated AAA + ATPase domain reduced estrogen-mediated induction of cyclin D1 and E2F1.
Wan et al. showed that ATAD2 is highly expressed in epithelial ovarian cancer tissues, and the degree of expression is positively correlated with the malignant degree of epithelial ovarian cancer tissues. In the HO-8910 and OVCAR-3 cell lines, ATAD2 was highly expressed, and the cell line was silenced by the ATAD2 expression, and the proliferation, invasion and migration ability of ovarian cancer cells were found to decrease. This indicates that ATAD2 may play an important role in the proliferation and invasion and migration of ovarian cancer cells. In addition, patients with epithelial ovarian cancer who were followed up showed that the 5-year survival rate of patients with high expression of ATAD2 was low, indicating that ATAD2 may be a prognostic marker and therapeutic target for ovarian cancer.