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AATF (anti-apoptotic transcription factor), is also called Che-1 and belongs to RNA polymerase II binding protein. It plays an important role in regulating gene transcription, cell proliferation, and apoptosis. The human AATF gene is located on chromosome 17q11.2-q12 and can transcribe a 2 023 bp AATF mRNA that encodes 561 amino acids. The gene product is an intranuclear protein. The AATF protein structure has an open reading frame consisting of 560 amino acids. AATF is expressed at high levels in the human brain, heart, thymus, kidney and placenta, and lower levels of expression in skeletal muscle and colon.
AATF not only plays an important role in the early embryonic development but also initiates a series of defense mechanisms to protect the body from stress or chronic injury. Moreover, AATF has a certain relationship with the occurrence and development of tumors.
AATF and DNA damage
When DNA damage occurs in the body, in response to erroneous DNA replication or chromatin separation, the body produces a series of cascade reactions to maintain gene integrity and minimize DNA damage, a process known as DNA damage response (DNA Damage response, DDR). DDR can provide the body with sufficient time for DNA repair, but if the body's DNA damage is so severe that the body is difficult to compensate, it will trigger apoptosis.
Figure 1. Che-1/AATF is a central mediator of the cellular response to different types of stress. (Iezzi, et al. 2015).
AATF is an important regulator of DNA damage-induced P53 response to tumor suppressor genes, and the P38-mitogen-activated protein kinase-activated protein kinase (MK) 2-AATF signaling pathway plays an important role in DDR. It was found that the amount of phosphorylated AATF on P53 and P21 promoters were significantly increased under the treatment of DNA damage drug doxorubicin. DNA damage induces ataxia-telangiectasis mutated (ATM) gene/Rad-3 related protein (ATR) and cell cycle checkpoint kinase (CHK)- 2 Phosphorylation so that AATF can remains stable to activates P53 and P21 transcription. Thus, AATF-P53 signal pathway in the DNA damage process has a complex mechanism and has an irreplaceable role for DDR.
X-linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitor of an apoptotic protein family, which selectively binds and inhibits caspase-3, -7, -9, and is a potentially therapeutic target for cancer therapy. A study found that on the XIAP promoter, the number of AATF was positively correlated with DNA damage, and down-regulation of AATF levels in human colon cancer cells by small interfering RNA technology can significantly reduce XIAP protein levels and inhibit transcription. After treatment with doxorubicin, cell XIAP levels increased. The XIAP level increased more significantly, especially in the AATF overexpression group, but in the small interference removal AATF group was not obvious. It can be seen that AATF and XIAP are closely related.
Tumor-susceptibility gene (TSG)101 is also a tumor suppressor and plays an important role in the regulation of ubiquitination. TSG101 and AATF are co-activators of androgen receptor-mediated transcription, and the activation effect is dose-dependent. When the C-terminal deletion of TSG101 interacts with AATF, the coactivating effect of both disappears. ATF, TSG101 and zipper-interacting protein kinase (ZIPK) 3 were considered as androgen receptor coactivators. Felten et al. used a chromosome co-immunoprecipitation method to find that the binding of AATF to ZIPK depends on the androgen receptor, whereas the binding of AATF to TSGl01 is dependent on AATF. Studies have shown that AATF acts on ZIPK through a leucine zipper structure, and the C-terminus of TSG101 interacts with AATF. The three LXXLL motifs of AATF promote their interaction with androgen receptors, which mutually promote steroid receptor-mediated hormone transcriptional activity. Neurotrophin receptor-associated melanoma antigen gene homolog (NRAGE) is a death-inducing agent that can block its intracellular components by interacting with AATF, inhibiting the nuclear localization of AATF. Xu et al. found that NRAGE plays an important role in the stress process of brain injury in adult rats. The expression of AATF in the cerebral cortex is up-regulated, and the NRAGE influences the intracellular localization. This process also involves the activation of caspase-3 apoptosis pathway. The above studies show that AATF can perform the opposite function of anti-apoptosis through NRAGE, and it is inducing apoptosis.
AATF and Diseases
AATF plays a very important role in the development of tumors. In the event of DNA damage, the activation of the monitoring site can promote DNA damage repair, but it also reduces the anti-tumor effect of chemotherapeutic drugs. Gao et al. showed that tumor cells often survive and proliferate due to lack of G1 monitoring sites. Removal of G2/M monitoring sites has a greater impact on the survival of tumor cells and less on normal cells. Therefore, proper inhibition of AATF facilitates the control of tumors.
AATF is over-expressed in leukemia cell lines, and its relationship with leukemia has attracted widespread attention. Lyu et al. used small interfering RNA technology to discover that down-regulation of AATF levels in leukemic cell lines increased the rate of cell apoptosis so that AATF may become leukemia therapeutic potential targets. SharmaL and other studies have shown that in breast cancer cells, AATF expression levels are higher. However, it is possible to downregulate the expression of estrogen receptors, up-regulate the expression of pro-apoptotic genes, induce apoptosis through the small interfering RNA technology to AATF expression. This process is also related to the NF-KB pathway.
The researchers performed P53 immunohistochemical staining on the lesions of patients with endometrial cancer. The results showed that patients with low levels of P53 staining had higher levels of nuclear AATF and lower survival rates. In patients with retinoblastoma, those with low AATF expression had higher survival rates than those with high expression. The above results suggest that AATF expression may be closely related to the prognosis of patients with cancer. In addition, AATF is not highly expressed in all tumor cells and it is expressed in some tumor cells, such as colon cancer cells and renal cancer cells.