* 152391

ARACHIDONATE 12-OXIDOREDUCTASE; ALOX12


Alternative titles; symbols

12-LIPOXYGENASE; LOG12
12LO


HGNC Approved Gene Symbol: ALOX12

Cytogenetic location: 17p13.1     Genomic coordinates (GRCh38): 17:6,996,049-7,010,754 (from NCBI)


TEXT

Description

The major pathway of arachidonic acid metabolism in human platelets proceeds via a 12-lipoxygenase enzyme (EC 1.13.11.31), which introduces a molecular oxygen into C-12 of arachidonic acid (summary by Funk et al., 1990).


Cloning and Expression

Using a combination of the polymerase chain reaction (PCR) and conventional screening procedures, Funk et al. (1990) isolated cDNA clones encoding the 12-lipoxygenase found in human platelets and in human erythroleukemia (HEL) cells. From the deduced primary structure, human platelet/HEL 12-lipoxygenase is predicted to encode a 663-amino acid protein with a molecular mass of 75,000 Da.

Izumi et al. (1990) isolated a full-length cDNA clone for 12-lipoxygenase from a human platelet cDNA library using a cDNA for human reticulocyte 15-lipoxygenase (ALOX15; 152392) as a probe in the initial screening. They reported that the cDNA had an open reading frame encoding 662 amino acid residues with a calculated molecular mass of 75,590 Da. The deduced sequence showed 65% identity with human reticulocyte 15-lipoxygenase and 42% identity with human leukocyte 5-lipoxygenase (ALOX5; 152390). Similar findings with cDNAs from human erythroleukemia cells were reported by Yoshimoto et al. (1990).


Gene Structure

Funk et al. (1992) determined that the ALOX12 gene contains 14 exons and spans approximately 15 kb of genomic DNA.


Mapping

By PCR analysis of a human-hamster somatic hybrid DNA panel, Funk et al. (1992) found that the LOG12 gene and a probable pseudogene map to chromosome 17. Funk et al. (1992) found that expression of one lipoxygenase gene could be detected in human erythroleukemia cells, platelets, and human umbilical vein endothelial cells. By reverse transcription-PCR analysis, there was no detectable expression of the second gene in several tissues and cell lines, supporting the notion that it represents a pseudogene.

By fluorescence in situ hybridization, Yoshimoto et al. (1992) mapped the ALOX12 gene to 17p13.1.


Gene Function

Natarajan et al. (1997) evaluated the regulation of LOG12 activity and expression in breast cancer cells and tissues. In each of 6 patients, the breast cancer-involved section showed a much higher level of LOG12 mRNA than the corresponding normal section. Also, LOG12 mRNA levels were greater in 2 breast cancer cell lines (MCF-7 and COH-BR1) compared with the nontumorigenic breast epithelial cell line, MCF-10F. They concluded that activation of the LOG12 pathway may play a key role in basal and EGF-induced breast cancer cell growth.

LOG12 gene expression in pancreatic beta cells is upregulated by cytotoxic cytokines such as interleukin-1-beta (IL1B; 147720). To evaluate the role of LOG12 gene expression in immune-mediated islet destruction, Bleich et al. (1999) used 12LO knockout mice. Male homozygous 12LO knockout mice and control C57BL/6 mice received 5 consecutive daily injections of streptozotocin to induce immune-mediated diabetes. They found that elimination of leukocyte 12LO in mice ameliorated low-dose streptozotocin-induced diabetes by increasing islet resistance to cytokines and decreasing macrophage production of nitric oxide.

Using recombinant proteins, Kutzner et al. (2017) showed that mammalian ALOX15 orthologs preferably oxygenated docosahexaenoic acid (DHA) in the presence of various polyunsaturated fatty acids. Human ALOX15 exhibited dual specificity with DHA, forming similar amounts of 14- and 17-hydroperoxides. In contrast, human ALOX12 and ALOX15B (603697) displayed singular specificity with DHA, forming 14- and 17-hydroperoxides, respectively.


REFERENCES

  1. Bleich, D., Chen, S., Zipser, B., Sun, D., Funk, C. D., Nadler, J. L. Resistance to type 1 diabetes induction in 12-lipoxygenase knockout mice. J. Clin. Invest. 103: 1431-1436, 1999. [PubMed: 10330425, images, related citations] [Full Text]

  2. Funk, C. D., Funk, L. B., FitzGerald, G. A., Samuelsson, B. Characterization of human 12-lipoxygenase genes. Proc. Nat. Acad. Sci. 89: 3962-3966, 1992. [PubMed: 1570320, related citations] [Full Text]

  3. Funk, C. D., Furci, L., FitzGerald, G. A. Molecular cloning, primary structure, and expression of the human platelet/erythroleukemia cell 12-lipoxygenase. Proc. Nat. Acad. Sci. 87: 5638-5642, 1990. [PubMed: 2377602, related citations] [Full Text]

  4. Izumi, T., Hoshiko, S., Radmark, O., Samuelsson, B. Cloning of the cDNA for human 12-lipoxygenase. Proc. Nat. Acad. Sci. 87: 7477-7481, 1990. [PubMed: 2217179, related citations] [Full Text]

  5. Kutzner, L., Goloshchapova, K., Heydeck, D., Stehling, S., Kuhn, H., Schebb, N. H. Mammalian ALOX15 orthologs exhibit pronounced dual positional specificity with docosahexaenoic acid. Biochim. Biophys. Acta Molec. Cell Biol. Lipids 1862: 666-675, 2017. [PubMed: 28400162, related citations] [Full Text]

  6. Natarajan, R., Esworthy, R., Bai, W., Gu, J.-L., Wilczynski, S., Nadler, J. Increased 12-lipoxygenase expression in breast cancer tissues and cells. Regulation by epidermal growth factor. J. Clin. Endocr. Metab. 82: 1790-1798, 1997. [PubMed: 9177384, related citations] [Full Text]

  7. Yoshimoto, T., Arakawa, T., Hada, T., Yamamoto, S., Takahashi, E. Structure and chromosomal localization of human arachidonate 12-lipoxygenase gene. J. Biol. Chem. 267: 24805-24809, 1992. [PubMed: 1447217, related citations]

  8. Yoshimoto, T., Yamamoto, Y., Arakawa, T., Suzuki, H., Yamamoto, S., Yokoyama, C., Tanabe, T., Toh, H. Molecular cloning and expression of human arachidonate 12-lipoxygenase. Biochem. Biophys. Res. Commun. 172: 1230-1235, 1990. [PubMed: 2244907, related citations] [Full Text]


Bao Lige - updated : 09/23/2019
Victor A. McKusick - updated : 7/6/1999
John A. Phillips, III - updated : 8/5/1997
Creation Date:
Victor A. McKusick : 8/23/1990
mgross : 09/23/2019
carol : 05/16/2014
jlewis : 7/15/1999
terry : 7/6/1999
alopez : 3/23/1999
jenny : 8/5/1997
carol : 5/12/1994
carol : 1/28/1993
carol : 7/6/1992
carol : 6/3/1992
supermim : 3/16/1992
carol : 12/9/1991

* 152391

ARACHIDONATE 12-OXIDOREDUCTASE; ALOX12


Alternative titles; symbols

12-LIPOXYGENASE; LOG12
12LO


HGNC Approved Gene Symbol: ALOX12

Cytogenetic location: 17p13.1     Genomic coordinates (GRCh38): 17:6,996,049-7,010,754 (from NCBI)


TEXT

Description

The major pathway of arachidonic acid metabolism in human platelets proceeds via a 12-lipoxygenase enzyme (EC 1.13.11.31), which introduces a molecular oxygen into C-12 of arachidonic acid (summary by Funk et al., 1990).


Cloning and Expression

Using a combination of the polymerase chain reaction (PCR) and conventional screening procedures, Funk et al. (1990) isolated cDNA clones encoding the 12-lipoxygenase found in human platelets and in human erythroleukemia (HEL) cells. From the deduced primary structure, human platelet/HEL 12-lipoxygenase is predicted to encode a 663-amino acid protein with a molecular mass of 75,000 Da.

Izumi et al. (1990) isolated a full-length cDNA clone for 12-lipoxygenase from a human platelet cDNA library using a cDNA for human reticulocyte 15-lipoxygenase (ALOX15; 152392) as a probe in the initial screening. They reported that the cDNA had an open reading frame encoding 662 amino acid residues with a calculated molecular mass of 75,590 Da. The deduced sequence showed 65% identity with human reticulocyte 15-lipoxygenase and 42% identity with human leukocyte 5-lipoxygenase (ALOX5; 152390). Similar findings with cDNAs from human erythroleukemia cells were reported by Yoshimoto et al. (1990).


Gene Structure

Funk et al. (1992) determined that the ALOX12 gene contains 14 exons and spans approximately 15 kb of genomic DNA.


Mapping

By PCR analysis of a human-hamster somatic hybrid DNA panel, Funk et al. (1992) found that the LOG12 gene and a probable pseudogene map to chromosome 17. Funk et al. (1992) found that expression of one lipoxygenase gene could be detected in human erythroleukemia cells, platelets, and human umbilical vein endothelial cells. By reverse transcription-PCR analysis, there was no detectable expression of the second gene in several tissues and cell lines, supporting the notion that it represents a pseudogene.

By fluorescence in situ hybridization, Yoshimoto et al. (1992) mapped the ALOX12 gene to 17p13.1.


Gene Function

Natarajan et al. (1997) evaluated the regulation of LOG12 activity and expression in breast cancer cells and tissues. In each of 6 patients, the breast cancer-involved section showed a much higher level of LOG12 mRNA than the corresponding normal section. Also, LOG12 mRNA levels were greater in 2 breast cancer cell lines (MCF-7 and COH-BR1) compared with the nontumorigenic breast epithelial cell line, MCF-10F. They concluded that activation of the LOG12 pathway may play a key role in basal and EGF-induced breast cancer cell growth.

LOG12 gene expression in pancreatic beta cells is upregulated by cytotoxic cytokines such as interleukin-1-beta (IL1B; 147720). To evaluate the role of LOG12 gene expression in immune-mediated islet destruction, Bleich et al. (1999) used 12LO knockout mice. Male homozygous 12LO knockout mice and control C57BL/6 mice received 5 consecutive daily injections of streptozotocin to induce immune-mediated diabetes. They found that elimination of leukocyte 12LO in mice ameliorated low-dose streptozotocin-induced diabetes by increasing islet resistance to cytokines and decreasing macrophage production of nitric oxide.

Using recombinant proteins, Kutzner et al. (2017) showed that mammalian ALOX15 orthologs preferably oxygenated docosahexaenoic acid (DHA) in the presence of various polyunsaturated fatty acids. Human ALOX15 exhibited dual specificity with DHA, forming similar amounts of 14- and 17-hydroperoxides. In contrast, human ALOX12 and ALOX15B (603697) displayed singular specificity with DHA, forming 14- and 17-hydroperoxides, respectively.


REFERENCES

  1. Bleich, D., Chen, S., Zipser, B., Sun, D., Funk, C. D., Nadler, J. L. Resistance to type 1 diabetes induction in 12-lipoxygenase knockout mice. J. Clin. Invest. 103: 1431-1436, 1999. [PubMed: 10330425] [Full Text: https://doi.org/10.1172/JCI5241]

  2. Funk, C. D., Funk, L. B., FitzGerald, G. A., Samuelsson, B. Characterization of human 12-lipoxygenase genes. Proc. Nat. Acad. Sci. 89: 3962-3966, 1992. [PubMed: 1570320] [Full Text: https://doi.org/10.1073/pnas.89.9.3962]

  3. Funk, C. D., Furci, L., FitzGerald, G. A. Molecular cloning, primary structure, and expression of the human platelet/erythroleukemia cell 12-lipoxygenase. Proc. Nat. Acad. Sci. 87: 5638-5642, 1990. [PubMed: 2377602] [Full Text: https://doi.org/10.1073/pnas.87.15.5638]

  4. Izumi, T., Hoshiko, S., Radmark, O., Samuelsson, B. Cloning of the cDNA for human 12-lipoxygenase. Proc. Nat. Acad. Sci. 87: 7477-7481, 1990. [PubMed: 2217179] [Full Text: https://doi.org/10.1073/pnas.87.19.7477]

  5. Kutzner, L., Goloshchapova, K., Heydeck, D., Stehling, S., Kuhn, H., Schebb, N. H. Mammalian ALOX15 orthologs exhibit pronounced dual positional specificity with docosahexaenoic acid. Biochim. Biophys. Acta Molec. Cell Biol. Lipids 1862: 666-675, 2017. [PubMed: 28400162] [Full Text: https://doi.org/10.1016/j.bbalip.2017.04.001]

  6. Natarajan, R., Esworthy, R., Bai, W., Gu, J.-L., Wilczynski, S., Nadler, J. Increased 12-lipoxygenase expression in breast cancer tissues and cells. Regulation by epidermal growth factor. J. Clin. Endocr. Metab. 82: 1790-1798, 1997. [PubMed: 9177384] [Full Text: https://doi.org/10.1210/jcem.82.6.3990]

  7. Yoshimoto, T., Arakawa, T., Hada, T., Yamamoto, S., Takahashi, E. Structure and chromosomal localization of human arachidonate 12-lipoxygenase gene. J. Biol. Chem. 267: 24805-24809, 1992. [PubMed: 1447217]

  8. Yoshimoto, T., Yamamoto, Y., Arakawa, T., Suzuki, H., Yamamoto, S., Yokoyama, C., Tanabe, T., Toh, H. Molecular cloning and expression of human arachidonate 12-lipoxygenase. Biochem. Biophys. Res. Commun. 172: 1230-1235, 1990. [PubMed: 2244907] [Full Text: https://doi.org/10.1016/0006-291x(90)91580-l]


Contributors:
Bao Lige - updated : 09/23/2019
Victor A. McKusick - updated : 7/6/1999
John A. Phillips, III - updated : 8/5/1997

Creation Date:
Victor A. McKusick : 8/23/1990

Edit History:
mgross : 09/23/2019
carol : 05/16/2014
jlewis : 7/15/1999
terry : 7/6/1999
alopez : 3/23/1999
jenny : 8/5/1997
carol : 5/12/1994
carol : 1/28/1993
carol : 7/6/1992
carol : 6/3/1992
supermim : 3/16/1992
carol : 12/9/1991