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axin1

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Official Full Name
axin 1
Background
Component of the beta-catenin destruction complex required for regulating CTNNB1 levels through phosphorylation and ubiquitination, and modulating Wnt-signaling. Controls dorsoventral patterning via two opposing effects; down-regulates CTNNB1 to inhibit the Wnt signaling pathway and ventralize embryos, but also dorsalizes embryos by activating a Wnt-independent JNK signaling pathway. In Wnt signaling, probably facilitates the phosphorylation of CTNNB1 and APC by GSK3B. Likely to function as a tumor suppressor. Facilitates the phosphorylation of TP53 by HIPK2 upon ultraviolet irradiation. Enhances TGF-beta signaling by recruiting the RNF111 E3 ubiquitin ligase and promoting the degradation of inhibitory SMAD7. Also component of the AXIN1-HIPK2-TP53 complex which controls cell growth, apoptosis and development.
Synonyms
AXIN1; axin 1; axin-1; PPP1R49; protein phosphatase 1; regulatory subunit 49; AI316800; AXIN; AXIN1_HUMAN; Axis inhibition protein 1; Axis Inhibitor 1; hAxin; Kb; Ki; kinky; knobbly; protein phosphatase 1, regulatory subunit 49; fused, mouse, homolog of; MGC52315; AXIN1-RGS; wu:fi22e03; wu:fj14c08; wu:fk11b03; zgc:109872; mbl; masterblind

Recent Research Progress

The AXIN family has two main members: AXIN1 (also referred to as AXIN) and AXIN2 (also known as axil or conductorin). AXIN1 was initially found to be associated with a dominant phenotype in mouse tail malformations. Subsequently, the researchers co-injected AXIN1 and Wnt pathway molecules into the ventral side of Xenopus embryos and found that AXIN1 negatively regulates Wnt signaling. An important function of AXIN1 in the Wnt pathway is to disrupt the assembly of the β-catenin complex, which in turn inhibits β-catenin-dependent target gene expression. Aberrant activation of the Wnt pathway is considered to be the major cause of colorectal cancer. Since AXIN1 negatively regulates the Wnt/β-catenin signaling pathway, AXIN1 has long been considered as a tumor suppressor gene.

AXIN1 and Wnt Signaling Pathways

The Wnt pathway controls the biological behavior of cells by modulating the transcriptional activity of DNA binding proteins in the TCF/LEF-1 family. Wnt ligands are secreted glycoproteins and LRP5 and LRP6 are basic receptors for Wnt ligands. When the Wnt signal is quiescent, TCF binds to the repressor protein and thereby inhibits the expression of the Wnt target gene. When the Wnt pathway is activated, β-catenin is activated in the cytoplasm, and it can bind to TCF to activate the target gene. When the Wnt pathway is quiescent, the serine residue of β-catenin is phosphorylated, which promotes the phosphorylation of the serine/threonine residue of glycogen synthase kinase 3β (GSK3β), while the phosphorylation of the latter proceeds through β-Tr CP triggers ubiquitination of β-catenin and degradation of the proteasome. The intracellular AXIN1, AXIN2 protein, tumor suppressor gene products APC, GSK3β, and CK1e also promote the phosphorylation and degradation of β-catenin.

Figure 1. The spatial and functional organization of the core mechanism of Wnt/β-catenin signaling. (Hayward, et al. 2012).

AXIN1 and TGF-β Signaling Pathways

TGF-β signaling also has important regulatory functions such as proliferation, differentiation, migration, apoptosis, and tumorigenesis. When TGF-β signaling is activated, TGF-β effector protein is phosphorylated and phosphorylated signal transduction molecules enter the nucleus, transcripting target genes in the nucleus. When the TGF-β signal is quiescent, R-signal transducing molecules are present in the cytoplasm through interactions with membrane-anchored proteins such as SARA and Hgs. SARA can interact with Smad2/Smad3 and promote its activation. Hgs can also cooperate with SARA to activate Smad2/Smad3. In the absence of receptor activation, AXIN1 acts similarly to SARA, and AXIN1 directly interacts with Smad3 and promotes Smad3 activation. Cell localization analysis of AXIN1 was performed similarly to SARA. AXIN1 was present in the cytoplasm and co-localized with Smad3. However, AXIN1 and SARA may be located independently in cytoplasm, and AXIN1 does not affect the interaction between Smad3 and SARA, nor does it co-precipitate with SARA. AXIN1 can promote the interaction between Smad3 and Tb R-I, phosphorylation of Tb R-I releases Smad3, and the released Smad3 forms a complex with Co-Smad into the nucleus involved in transcriptional regulation.

AXIN1 Regulates P53 Gene

It is well-known that p53 is the tumor suppressor gene discovered so far that is most closely related to tumor development and plays an important role in regulating cell proliferation and apoptosis. AXIN1 phosphorylates p53 serine by binding to homeodomain interacting protein kinase 2 (HIPK2) and selectively increases transcriptional activity of p53-dependent target genes, thereby suppressing tumorigenesis.

AXIN1 and Tumor

AXIN1 plays a role in cell proliferation, differentiation, and apoptosis by participating in multiple signal transduction pathways. Moreover, it plays an important role in the occurrence and development of many tumors. The mutation of AXIN1 is highly correlated with the onset of colorectal cancer, and multiple mutations have been included in the SNP database. As a result, it can serve as a predictive target for the risk of colorectal cancer. Yang et al. reported that AXIN1 was downregulated in many lung cancer cases, and X-ray irradiation increased AXIN1 expression and inhibited lung cancer cells. Lung cancer cells with different methylation status of AXIN1 gene showed different radiosensitivity, indicating that the methylation status of AXIN1 gene may be an important factor in predicting tumor radiosensitivity.

Li et al. studied the role of AXIN1 in tumorigenesis and progression of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and found that AXIN1 overexpression negatively regulates β-catenin-dependent transcriptional activity and downregulates cell cycle regulation. Protein levels indicate that AXIN1 may be a potential target for primary HCC gene therapy. Autophagy is a pathophysiological phenomenon in liver cirrhosis that can further develop into liver cancer. Pu et al. investigated the relationship between the AXIN1 polymorphism and the susceptibility of clear cell renal cell carcinoma (ccRCC), suggesting that the rs1805105 CT/CC genotype and rs12921862 AA genotype may be involved in ccRCC development. Therefore, AXIN1 does have an important role in suppressing tumorigenesis and development. It also indicates that the discovery and mastery of the AXIN1 gene's regulatory mechanism of tumors can promote AXIN1 protein as a new reference for the diagnosis of tumors and the evaluation of prognosis. AXIN1 also provides a new basis for tumor gene therapy and targeted drugs.

Reference:

  1. Aristizabalpachon A F, Carvalho T I, Carrara H H, et al. AXIN2 Polymorphisms, the β-Catenin Destruction Complex Expression Profile and Breast Cancer Susceptibility.. Asian Pacific Journal of Cancer Prevention Apjcp, 2015, 16(16):7277-84.
  2. Yang L H, Han Y, Li G, et al. Axin gene methylation status correlates with radiosensitivity of lung cancer cells. BMC Cancer. 2013, 13(1):1-12.
  3. Li J, Quan H, Liu Q, et al. Alterations of axis inhibition protein 1 (AXIN1) in hepatitis B virus-related hepatocellular carcinoma and overexpression of AXIN1 induces apoptosis in hepatocellular cancer cells.. Oncology Research, 2013, 20(7):281-288.
  4. Pu Y, Mi X, Chen P, et al. Genetic association of polymorphisms in AXIN1 gene with clear cell renal cell carcinoma in a Chinese population. Biomarkers in Medicine, 2017(176).
  5. Hayward P, Kalmar T, Arias A M. Wnt/Notch signalling and information processing during development. Development, 2008, 135(3):411-424.