AKNA

Detailed Information

AKNA (AT-hook transcription factor) is an intranuclear protein with an AT-hook motif. The AT-hook protein was first discovered in the mammalian non-histone chromosomal high-mobility group protein HMG-I/Y. The AT-hook protein family mainly includes the high mobility group protein (HMG) family. Human AKNA is a transcription factor with an AT-hook motif at the N-terminus and C-terminus, while the mouse AKNA has an AT-hook motif at the N-terminus and an AT-hook-like motif (ALM) at the C-terminus. The human AKNA gene is 63bp in length and contains 24 exons and 2 polyadenylation sites encoding 9 different transcripts. Human AKNA also has three PEST (proline-glutamate-serine-threonine) regions, and the PEST sequence is closely related to the stability of nuclear proteins, so AKAN can be stably present in the nucleus.

The main structural feature of the AT-hook protein motif is a small motif centered on the arginine-glycine-arginine-valine (RGRP) four amino acid residues, so the AT-hook protein motif is also known as RGRP motif. AKNA consists of a 9 amino acid domain with an amino acid sequence of RTRGRPADS, which is consistent with the AT-hook protein DNA binding motif. At the same time, this short conserved amino acid sequence is essential for the localization of the AT-hook protein. The AT-hook protein combines with the AT-base-rich DNA region through an amino acid motif to coordinate the transcription of the promoter by modifying the structure of the DNA to increase the activity of the promoter that binds to the transcription factor.

Martíneznava et al. found that the transcription factor AKNA is mainly expressed on B lymphocytes, T lymphocytes, natural killer cells and stem cells, and plays a crucial role in the immune response. In recent years, studies have found that knocking out the AKNA gene can lead to severe lung injury, neutrophil-mediated inflammatory response, and fetal growth retardation. In addition, loss of AKNA function directly leads to cervical neoplastic lesions. It can be seen that AKNA is closely related to human health and plays a decisive role in the occurrence and development of diseases.

The Biological Function of AKNA

Inducing Tumorigenic Transformation

The relationship between AKNA and neoplastic disease is a hot topic in current research. Qin et al. reported that the high mobility group protein A1 (HMGA1) belonging to the AT-hook protein family is overexpressed in breast cancer, bladder cancer, and brain cancer. This overexpression activates the inflammatory pathway and promotes carcinogenic transformation. Therefore, it is speculated that AKNA may have a similar effect to HMGA1. It has been reported that the 9q32 region where AKNA is located on the human chromosome contains a cervical cancer susceptibility site. The AT-hook domain single nucleotide polymorphism (SNP) on the transcription factor AKNA increases the risk of cervical cancer, and also indicates that loss of AKNA function can potentially increase human papillomavirus (HPV)-mediated inflammation, thereby promoting cervical neoplastic lesions. The expression level of AKNA is also related to the polymorphism of the promoter associated with cervical cancer.

Chronic inflammation is a common and important factor in the pathogenesis of tumors. It develops into cancer under the action of toxicological factors or under inflammatory pathological conditions. Helicobacter pylori can cause gastric cancer, and the gastroesophageal reflux disease department causes malignant adenoma. Therefore, there is an upstream and downstream relationship between transcription factor AKNA, inflammation and cervical cancer. Removal of AKNA can increase HPV-mediated inflammation, which can induce cervical cancer, and cervical cancer-related promoters in turn also affect the expression level of AKNA.

Participate in the Occurrence of Inflammatory Reactions

Acute and neoplastic diseases can lead to neutrophil-mediated inflammation, and the AKNA gene may be one of the decisive risk factors. Human AKNA is encoded by a single gene located in the sensitive region of the chromosome fragile site 9q32, whereas dysfunctional mutations in fragile sites often lead to inflammatory and neoplastic diseases. The mouse AKNA gene is located on the fragile site of the FRA4C2 fragility site, which is frequently altered in inflammatory responses and cancer. AKNA is closely related to inflammatory responses and tumor formation. When the AKNA gene is knocked out, it can cause death and neutrophil inflammatory response in newborn mice, while protecting the body from the harmful effects of inflammation when restoring AKNA function. Thus, AKNA plays an important role in the inflammatory response.

Figure 1. AKNA in the mechanism of T-2 toxin-mediated growth inhibition. (Liu, et al. 2016).

Functional Regulation of AKNA

AKNA is an important transcription factor regulating the expression of key receptor-ligands, which up-regulates the expression of CD40 on the surface of T cells and B cells, and has important physiological significance during the secondary immune response. In the experiment of knocking out the AKNA gene leading to severe pneumonia, it was found that the expression levels of matrix metalloproteinase-9 (MMP-9), interleukin-1β (IL-1β), interferon-γ (IFN-γ), antibacterial peptide protein (CRAMP) ), neutrophil (NGP) and S100A9 genes are increased. In particular, MMP-9 expression was three times higher in wild-type mice in mice knocked out of the AKNA gene because AKNA inhibited the expression of the MMP-9 promoter-driven gene.

The MMP-9, IL-1β, IFN-γ, NGP, CRAMP and S100A9 promoters have an AT base sequence that binds to the transcription factor AKNA and satisfies the conditions for binding to the AT-hook protein. NGP is an important component of neutrophils and is involved in neutrophil-mediated lung inflammation. CRAMP is an angiogenesis-related protein that is involved in the transfer of neutrophils after activation by MMP, leading to the infiltration of neutrophils in the lungs.

S100A9 is a member of the calcium-binding protein family whose activity is regulated by the proteolytic process of MMP-9 and is involved in the enrichment of neutrophils in the microenvironment of the lung inflammation. MMP-9 belongs to neutrophil collagenase, which activates IL-1β expression, while IL-1β can aggregate neutrophils into the lungs to cause lung damage. MMP-9 is involved in lung injury and inflammatory response, and the MMP gene (MMP-2, MMP-9, MMP-13) is also a downstream substance of the AT-hook protein HMGA1, suggesting that it may also be a downstream substance of the transcription factor AKNA. AKNA can promote the development of inflammation, and inflammation is often an important precancerous lesion of many cancers. However, the upstream and downstream relationship and mechanism of AKNA transcription factors are still unclear and need further study.