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ALDH1A2

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ALDH1A2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesALDH1A2, RALDH(II), RALDH2, RALDH2-T, aldehyde dehydrogenase 1 family member A2
External IDsOMIM: 603687; MGI: 107928; HomoloGene: 68368; GeneCards: ALDH1A2; OMA:ALDH1A2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

8854

19378

Ensembl

ENSG00000128918

ENSMUSG00000013584

UniProt

O94788

Q62148

RefSeq (mRNA)

NM_170697
NM_001206897
NM_003888
NM_170696

NM_009022

RefSeq (protein)

NP_001193826
NP_003879
NP_733797
NP_733798

NP_033048

Location (UCSC)Chr 15: 57.95 – 58.5 MbChr 9: 71.12 – 71.2 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
ALDH1A2 expressed from Aldehyde Dehydrogenase (ALDH)

Aldehyde dehydrogenase 1 family, member A2, also known as ALDH1A2 or retinaldehyde dehydrogenase 2 (RALDH2), is an enzyme that in humans is encoded by the ALDH1A2 gene.[5][6]

Function

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ALDH1a2 belongs to the aldehyde dehydrogenase family of proteins, and specifically the ALDH1 family. The product of this gene, ALDH1a2, is an enzyme that catalyzes the synthesis of all-trans retinoic acid (RA) from retinaldehyde in a NAD-dependent manner.[7] Retinoic acid, the active derivative of vitamin A (retinol), is a retinoid nuclear receptor ligand that functions in developing and adult tissues.[8]

ALDH1a2 is critical to fetal development by activating the RAR nuclear receptors. Studies of ALDH1a2 in mice suggest that this enzyme and the cytochrome CYP26A1 enzyme coordinate local embryonic retinoic acid levels that facilitate posterior organ development and prevent spina bifida.[9]

In adult tissues, ALDH1a2 is know to regulate immune tolerance in the colon and other mucosal tissues by generating retinoic acid as a paracrine signal to CD4 T cells.[10] ALDH1a2 also works in conjunction with ALDH1a1 to establish sufficient retinoic acid levels in the testes to support spermatogenesis.[11] Due to its role in suppressing immune cells as well as its unique amplification in T cell Acute Lymphoblastic Leukemia (T-ALL), ALDH1a2 has been suggested as a target for cancer therapy.

Clinical significance

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Involvement in T-ALL

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ALDH1A2 is abnormally amplified in more than half of instances of T-cell acute lymphoblastic leukemia (T-ALL).[12] T-ALL is a leukemia that arises from immature T-cell precursors and is an aggressive form of cancer that primarily affects children but also occurs in adults. T-ALL is caused when one or more genes encoding transcription factors including TAL1, TLX1, HOXA, TAL2, LYL1, LMO1, LMO2, or NKX3 are genetically fused to other chromosomal regions. ALDH1A2 is one of the recognized downstream targets of TAL1 fusion genes which works by binding to the intronic regulatory element of ALDH1a2, thereby inducing a T-ALL specific isoform with enzymatic activity.[13] TAL-1 positive T-ALL accounts for approximately 40-60% of all primary T-ALL cases. According to researchers’ data, depletion of ALDH1A2 in T-ALL led to reduced cell viability in T-cell lines and caused apoptosis.[12]

Involvement in solid tumors

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ALDH1a2 is not expressed in most cancer cells and comparison studies reveal that it is often expressed at lower levels in tumors compared to adjacent normal tissues.[14] This contrasts with the related family members ALDH1a1 and ALDH1a3. For instance, the ALDH1A2 promoter region is hypermethylated in primary prostate tumors compared with normal prostate specimens, resulting in lower ALDH1a2 expression in prostate cancers.[15] In contrast to tumor cells, ALDH1a2 is expressed in many monocyte-derived populations known to reside in tumors such as alternatively activated macrophages and other antigen presenting cells.[16] Glioblastoma-associated macrophages highly express ALDH1A2 when compared to other ALDH family enzymes and this higher expression is associated with tumor recurrence.[17]

Population genetic studies

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ALDH1a2 is key regulator of development due to its role in producing retinoic acid in the developing fetus. Key organs affected by ALDH1a2 during development include the heart and neural tube.[7] Several small population studies have examined a link between single nucleotide polymorphisms in the ALDH1A2 gene and various disease states. In a case control study of 103 patients with congenital heart disease, ALDH1a2 SNPs were identified in patients, but the levels did not significantly differ from case controls[18] suggesting known ALDH1a2 polymorphisms do not affect risk of congenital heart disease.

In contrast, SNPs found in ALDH1a2 introns show statistically significant associations with hand osteoarthritis.[19] Extensive characterization of these loci show that SNPs associated with hand osteoarthritis result in quantitative reductions of ALDH1a2 expression, suggesting that ALDH1a2 protects against synovial inflammation.[19] 

 

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000128918 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000013584 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Ono Y, Fukuhara N, Yoshie O (December 1998). "TAL1 and LIM-only proteins synergistically induce retinaldehyde dehydrogenase 2 expression in T-cell acute lymphoblastic leukemia by acting as cofactors for GATA3". Molecular and Cellular Biology. 18 (12): 6939–6950. doi:10.1128/MCB.18.12.6939. PMC 109277. PMID 9819382.
  6. ^ "Entrez Gene: ALDH1A2 aldehyde dehydrogenase 1 family, member A2".
  7. ^ a b Mic FA, Molotkov A, Benbrook DM, Duester G (June 2003). "Retinoid activation of retinoic acid receptor but not retinoid X receptor is sufficient to rescue lethal defect in retinoic acid synthesis". Proceedings of the National Academy of Sciences of the United States of America. 100 (12): 7135–7140. Bibcode:2003PNAS..100.7135M. doi:10.1073/pnas.1231422100. PMC 165842. PMID 12782789.
  8. ^ Duester G (September 2008). "Retinoic acid synthesis and signaling during early organogenesis". Cell. 134 (6): 921–931. doi:10.1016/j.cell.2008.09.002. PMC 2632951. PMID 18805086.
  9. ^ Niederreither K, Abu-Abed S, Schuhbaur B, Petkovich M, Chambon P, Dollé P (May 2002). "Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development". Nature Genetics. 31 (1): 84–88. doi:10.1038/ng876. PMID 11953746.
  10. ^ Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, et al. (July 2007). "Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid". Science. 317 (5835): 256–260. doi:10.1126/science.1145697. PMID 17569825.
  11. ^ Topping T, Griswold MD (2022). "Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis". Frontiers in Endocrinology. 13: 871225. doi:10.3389/fendo.2022.871225. PMC 9097449. PMID 35574006.
  12. ^ a b Zhang C, Amanda S, Wang C, King Tan T, Zulfaqar Ali M, Zhong Leong W, et al. (June 2021). "Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia". Haematologica. 106 (6): 1545–1558. doi:10.3324/haematol.2019.245639. PMC 8168519. PMID 32414855.
  13. ^ Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson MR, et al. (August 2017). "The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia". Nature Genetics. 49 (8): 1211–1218. doi:10.1038/ng.3909. PMC 5535770. PMID 28671688.
  14. ^ "Expression of ALDH1A2 in cancer - Summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2024-12-03.
  15. ^ Kim H, Lapointe J, Kaygusuz G, Ong DE, Li C, van de Rijn M, et al. (September 2005). "The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer". Cancer Research. 65 (18): 8118–8124. doi:10.1158/0008-5472.CAN-04-4562. PMID 16166285.
  16. ^ Yokota-Nakatsuma A, Ohoka Y, Takeuchi H, Song SY, Iwata M (November 2016). "Beta 1-integrin ligation and TLR ligation enhance GM-CSF-induced ALDH1A2 expression in dendritic cells, but differentially regulate their anti-inflammatory properties". Scientific Reports. 6 (1): 37914. Bibcode:2016NatSR...637914Y. doi:10.1038/srep37914. PMC 5126582. PMID 27897208.
  17. ^ Kim H, Lapointe J, Kaygusuz G, Ong DE, Li C, van de Rijn M, et al. (September 2005). "The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer". Cancer Research. 65 (18): 8118–8124. doi:10.1158/0008-5472.CAN-04-4562. PMID 16166285.
  18. ^ Pavan M, Ruiz VF, Silva FA, Sobreira TJ, Cravo RM, Vasconcelos M, et al. (November 2009). "ALDH1A2 (RALDH2) genetic variation in human congenital heart disease". BMC Medical Genetics. 10: 113. doi:10.1186/1471-2350-10-113. PMC 2779186. PMID 19886994.
  19. ^ a b Shepherd C, Zhu D, Skelton AJ, Combe J, Threadgold H, Zhu L, et al. (October 2018). "Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant". Arthritis & Rheumatology. 70 (10): 1577–1587. doi:10.1002/art.40545. PMC 6175168. PMID 29732726.
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Further reading

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