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CYP11A1

Official Full Name
cytochrome P450 family 11 subfamily A member 1
Organism
Homo sapiens
GeneID
1583
Background
This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the mitochondrial inner membrane and catalyzes the conversion of cholesterol to pregnenolone, the first and rate-limiting step in the synthesis of the steroid hormones. Two transcript variants encoding different isoforms have been found for this gene. The cellular location of the smaller isoform is unclear since it lacks the mitochondrial-targeting transit peptide. [provided by RefSeq, Jul 2008]
Synonyms
CYP11A; CYPXIA1; P450SCC;
Bio Chemical Class
Paired donor oxygen oxidoreductase
Protein Sequence
MLAKGLPPRSVLVKGCQTFLSAPREGLGRLRVPTGEGAGISTRSPRPFNEIPSPGDNGWLNLYHFWRETGTHKVHLHHVQNFQKYGPIYREKLGNVESVYVIDPEDVALLFKSEGPNPERFLIPPWVAYHQYYQRPIGVLLKKSAAWKKDRVALNQEVMAPEATKNFLPLLDAVSRDFVSVLHRRIKKAGSGNYSGDISDDLFRFAFESITNVIFGERQGMLEEVVNPEAQRFIDAIYQMFHTSVPMLNLPPDLFRLFRTKTWKDHVAAWDVIFSKADIYTQNFYWELRQKGSVHHDYRGILYRLLGDSKMSFEDIKANVTEMLAGGVDTTSMTLQWHLYEMARNLKVQDMLRAEVLAARHQAQGDMATMLQLVPLLKASIKETLRLHPISVTLQRYLVNDLVLRDYMIPAKTLVQVAIYALGREPTFFFDPENFDPTRWLSKDKNITYFRNLGFGWGVRQCLGRRIAELEMTIFLINMLENFRVEIQHLSDVGTTFNLILMPEKPISFTFWPFNQEATQQ
Open
Disease
Cushing syndrome, Prostate cancer
Approved Drug
1 +
Clinical Trial Drug
1 +
Discontinued Drug
0

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Detailed Information

The CXCR2 gene (C-X-C motif chemokine receptor 2) is part of the G protein-coupled receptor (GPCR) family, playing crucial roles in immune and inflammatory responses. As a receptor for IL-8 (interleukin-8) and other chemokines, CXCR2 is essential for many physiological and pathological processes. This text provides an in-depth analysis of the CXCR2 gene, its target mechanisms, regulation, and role in diseases.

Structure and Function of the CXCR2 Gene

Located in the q34-q35 region of human chromosome 2, the CXCR2 gene clusters with the CXCR1 gene and the CXCR2P1 pseudogene. Comprised of 11 exons, the CXCR2 gene encodes a membrane-bound G protein-coupled receptor. This receptor, by binding chemokines such as IL-8 and CXCL1, activates the intracellular G protein-phosphoinositol-calcium signaling pathway to promote cell migration and its roles in inflammation and immune responses. Notably, its high-affinity binding to IL-8 directly participates in leukocyte chemotaxis, effectively regulating immune cell function and localization.

Figure 1: The CYP11A1 promoter region includes a proximal promoter with TATA, SF1, and Sp1 sites.Figure 1. The CYP11A1 promoter features key elements, including TATA, SF1, Sp1 sites, negative and adrenal-specific regions, and a cAMP-responsive sequence. (Guo IC., et al., 2003)

In addition, CXCR2 can bind other chemokines like CXCL3 (GRO) and NAP-2, regulating migration and positioning of various cell types, with significant implications in the tumor microenvironment. For example, CXCR2's vital role in melanoma cell growth, especially in serum-dependent melanoma growth, has been demonstrated. The signaling mechanism of CXCR2 involves coupling with G proteins to activate secondary messenger systems, thereby modulating numerous cellular reactions, particularly neutrophil migration and aggregation.

CXCR2 Signaling and Cell Migration

CXCR2 activates a series of signaling pathways upon ligand binding. In neutrophil chemotaxis, IL-8 binding to CXCR2 facilitates G protein activation, which then activates phosphoinositol-calcium channels, raising intracellular calcium levels and triggering cell migration responses. This process is significant in various immune responses, especially during acute inflammation, where CXCR2 guides immune cells to infection or injury sites.

Moreover, CXCR2 plays a crucial role in angiogenesis. For instance, IL-8 promotes angiogenesis in intestinal microvascular endothelial cells through CXCR2 receptors. This mechanism is also vital in tumor angiogenesis and spread, making CXCR2 a key regulator in the tumor immune microenvironment.

Regulation of CXCR2 Gene Expression

Several elements regulate CXCR2 gene expression. TATA and CAAT boxes as well as sites for transcription factors like NF-κB, which are vital in many physiological states, particularly during inflammatory reactions and cellular stress, abound in its promoter region. Under hypoxic circumstances, for instance, CXCR2 expression is increased—a process intimately related to the activities of hypoxia-inducible factor (HIF-1) and NF-κB.

Additionally controlling CXCR2 expression are hormones including mineralocorticoids and glucocorticoids. Studies reveal that related transcription factors and the cAMP signaling pathway may control CXCR2 expression in certain tissues, therefore affecting physiological processes like immunological responses and cell migration.

Role of CXCR2 in Diseases

Particularly in immunological inflammatory responses, tumor biology, and autoimmune illnesses, the CXCR2 receptor is essential in many diseases. CXCR2 helps neutrophils be directed to infected or injured areas in acute inflammatory reactions, therefore enabling the body to respond to pathogen invasion or tissue damage. On the other hand, too much CXCR2 activation might cause immunological dysregulation and persistent inflammation, therefore aggravating the course of illness.

High expression of CXCR2 and its ligand IL-8 is often linked in the tumor microenvironment to tumor development and dissemination. Apart from encouraging tumor cell migration and invasion, CXCR2 improves angiogenesis, thereby supplying the required blood for the malignancies. As a result, in tumor immunotherapy, CXCR2 is seen as a possible target. Particularly in tumors like melanoma and non-small cell lung cancer, studies demonstrate that suppressing CXCR2 expression or its signaling pathways may dramatically slow down tumor development and metastases, therefore displaying potential therapeutic outcomes.

Moreover, CXCR2's role in autoimmune diseases has garnered extensive attention. In several autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus, too high CXCR2 activation may cause aberrant immune responses and aggravation of tissue destruction. For these disorders, then, pharmacological treatments aiming at CXCR2 provide a fresh therapeutic approach.

Development Prospects of CXCR2-Targeted Therapy

More CXCR2-targeted therapy approaches are being developed as knowledge of the gene and its receptor roles advances. Two main directions of current research are: blocking CXCR2-mediated angiogenesis pathways to stop tumor cell dissemination and metastases; and reducing CXCR2 activity by small molecule inhibitors or antibody drugs to lower neutrophiliter migration and so minimize inflammatory responses.

Especially in the realm of cancer immunotherapy, CXCR2 inhibitors like anti-CXCR2 monoclonal antibodies and small molecule inhibitors have shown encouraging outcomes in early clinical trials. Combining CXCR2-targeted medicines with immune checkpoint inhibitors hopes to boost anti-tumor immune responses and improve patient clinical outcomes.

References:

  1. Chien Y, Rosal K, et al. Function of CYP11A1 in the mitochondria. Mol Cell Endocrinol. 2017 Feb 5;441:55-61.
  2. Guo IC, Hu MC, et al. Transcriptional regulation of CYP11A1. J Biomed Sci. 2003;10(6 Pt 1):593-8.
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