Disease relevance of Cyp26a1

• Aldh1a2 haploinsufficiency prevents the appearance of spina bifida and rescues the development of posterior structures (sacral/caudal vertebrae, hindgut, urogenital tract), while partly preventing cervical vertebral transformations and hindbrain pattern alterations in Cyp26a1(-/-) mice [1].
• Cyp26 genes a1, b1 and c1 are down-regulated in Tbx1 null mice and inhibition of Cyp26 enzyme function produces a phenocopy of DiGeorge Syndrome in the chick [2].
• Mouse liver CYP2C39 is a novel retinoic acid 4-hydroxylase. Its down-regulation offers a molecular basis for liver retinoid accumulation and fibrosis in aryl hydrocarbon receptor-null mice [3].

High impact information on Cyp26a1

• This hypothesis suggests that the Cyp26a1(-/-) phenotype could be rescued under conditions in which embryonic retinoic acid levels are decreased [1].
• P450RA metabolizes other biologically active RAs such as 9-cis RA and 13-cis RA, but fails to metabolize their precursors, retinol and retinal [4].
• Here we have identified a novel cytochrome P450 (P450RA) that specifically metabolizes RA [4].
• Ret-NH2 interacts only at micromolar concentrations with retinoic acid receptor, does not activate retinoid-X receptor, and is not a substrate for CYP26s, the retinoic acid-metabolizing cytochrome P450 enzymes [5].
• 5. Using real-time PCR and in situ hybridization analysis of Cyp26a1 and its two functionally related family members Cyp26b1 and c1, we demonstrate reduced and/or altered expression for all three genes in pharyngeal tissues of Tbx1 null embryos [2].

Chemical compound and disease context of Cyp26a1

• We have previously reported that the retinoic acid (RA) catabolizing enzyme CYP26A1 plays an important role in protecting tail bud tissues from inappropriate exposure to RA generated in the adjacent trunk tissues by RALDH2, and that Cyp26a1-null animals exhibit spina bifida and caudal agenesis [6].

Biological context of Cyp26a1

• Cyp26a1, a gene required for retinoic acid (RA) inactivation during embryogenesis, was previously identified as a potential Tbx1 target from a microarray screen comparing wild-type and null Tbx1 mouse embryo pharyngeal arches (pa) at E9 [2].
• We found that both RARbeta2 and Cyp26a1 genes are epigenetically silenced in the absence of DNA methylation in RAC65, a P19 embryocarcinoma cell line derivative carrying a dominant-negative RARalpha mutant and resistant to the growth-inhibitory and differentiation effects of RA [7].
• Knocking down RARbeta2 transcription by RNA interference in wild-type P19 cells, with an intact RARalpha, induced Cyp26a1 transcriptional repression in the absence of DNA methylation [7].
• Nevertheless, further airway branching appears to require downregulation of RA pathways by decreased synthesis, increased RA degradation in the epithelium via P450RAI-mediated metabolism, and inhibition of RA signaling in the mesenchyme by COUPTF-II expression [8].
• Deletion and mutational analyses of the P450RAI promoter, as well as DNase I footprinting studies, revealed potential binding sites for several other proteins in conserved regions of the promoter [9].

Anatomical context of Cyp26a1

• We demonstrate in mouse embryos that an RA signal initially travels from the paraxial mesoderm to r3, forming a boundary next to the r2 expression domain of Cyp26a1 (which encodes an RA-degrading enzyme) [10].
• Like its human and zibrafish counterparts, the mouse P450RAI cDNA catalyzes metabolism of retinoic acid into 4-OH-retinoic acid, 4-oxo-retinoic acid, 18-OH-retinoic acid, and unidentified water-soluble metabolites when transfected into COS-1 cells [11].
• Initially, both RALDH2 and RARE-LacZ activity were restricted to the sinus venosa in unlooped hearts, but were high in the dorsal mesocardium, while P450RA expression was restricted to the endocardium [12].

Associations of Cyp26a1 with chemical compounds

• We now show that, in the absence of Cyp26a1, retinoic acid receptor gamma (RARgamma) mediates ectopic RA-signaling in the tail bud [6].
• Regulation of CYP26 (cytochrome P450RAI) mRNA expression and retinoic acid metabolism by retinoids and dietary vitamin A in liver of mice and rats [13].
• Activation of a lacZ transgene controlled by an RA response element (RARE) was compared to the localization of the retinaldehyde-oxidizing dehydrogenase RALDH2, the earliest RA synthetic enzyme in the mouse embryo, and to the expression of a gene encoding an RA-degrading enzyme (P450RA) [12].

Regulatory relationships of Cyp26a1

• Similarly, we found that Cyp26a1 transcription is epigenetically regulated by RARbeta2 [7].

Other interactions of Cyp26a1

• Developing with lethal RA levels: genetic ablation of Rarg can restore the viability of mice lacking Cyp26a1 [6].
• Our findings suggest that Raldh2 and Cyp26 generate shifting boundaries of RA activity, such that r3-r4 receives a short pulse of RA and r5-r8 receives a long pulse of RA [10].
• Apparently, RARalpha, RARbeta2 and Cyp26a1 are components of a RA-regulated gene network [7].
• While RA applications increased retinal Cyp26a1 expression, they slightly reduced Cyp26c1 [14].

Analytical, diagnostic and therapeutic context of Cyp26a1

• Overexpression of P450RA in cell culture renders the cells hyposensitive to all-trans RA [4].
• Quantitative RT-PCR analysis and Western blot data revealed that the expression of CYP26s was much higher than that of Raldhs at early embryonic ages but that Cyp26 expression was downregulated during embryonic development [15].
• Sequence analysis of the proximal upstream region of the P450RAI promoter revealed a high degree of conservation between zebrafish, mouse, and human [9].

References