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Gene Review:

ALOX15B - arachidonate 15-lipoxygenase, type B

Homo sapiens

Synonyms: 15-LOX-2, 15-LOX-B, 15-lipoxygenase 2, Arachidonate 15-lipoxygenase B, Arachidonate 15-lipoxygenase type II, ...

Shappell, S.B. et al., Shureiqi, I. et al., Bhatia, B. et al., Shappell, S.B. et al., Tang, S. et al., et al.

Shureiqi, Wu, Chen, Yang, Guan, Morris, Yang, Newman, Broaddus, Hamilton, Lynch, Levin, Fischer, Lippman, Chang, Schneider, Roberts, Shappell, Haselton, Boeglin, Brash, Shappell, Gupta, Manning, Whitehead, Boeglin, Schneider, Case, Price, Jack, Wheeler, Matusik, Brash, Dubois, Shappell, Boeglin, Olson, Kasper, Brash, Krieg, Marks, Fürstenberger, Xu, Shappell, Liang, Song, Menter, Subbarayan, Iyengar, Tang, Lippman,

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Disease relevance of ALOX15B

In FAP patients, 15-LOX-1 expression and activity were significantly down-regulated in adenomas (compared with paired nonneoplastic epithelial mucosa), whereas 5-LOX and 15-LOX-2 protein expressions and enzymatic activities were not [1].
These results provide a plausible mechanism to explain the apparent opposing effects 15-LOX-1 and 15-LOX-2 play in prostate cancer [2].
This compares with the prostate, in which 15-lipoxygenase-2 is expressed in differentiated prostate secretory cells (and reduced in the majority of prostate adenocarcinomas) [3].
In the eyelid, Meibomian glands were uniformly negative for 15-lipoxygenase-2 in all cases examined (n = 9), and sebaceous carcinomas apparently derived from Meibomian glands were also negative (n = 12) [3].
Further investigation of the effects of nonsteroidal anti-inflammatory drugs on 15-LOX-2 expression and apoptosis in esophageal cancer cells may be warranted [4].

High impact information on ALOX15B

The very limited current data on the role of lipoxygenase (LOX) metabolism in tumorigenesis suggests that the oxidative metabolism of linoleic and arachidonic acid possibly shifts from producing antitumorigenic 15-LOX-1 and 15-LOX-2 products to producing protumorigenic 5-LOX and 12-LOX products [1].
Restoring terminal differentiation and apoptosis of Caco-2 cells increased the mRNA levels of 5-LOX, 15-LOX-2, and 15-LOX-1, but the only significant increases in protein expression and enzymatic activity were of 15-LOX-1 [1].
These results support the hypothesis that 15-LOX-2-derived 15S-HETE may constitute an endogenous ligand for PPARgamma in the prostate and that loss of this pathway by reduced expression of 15-LOX-2 may contribute to increased proliferation and reduced differentiation in prostate carcinoma [5].
Immunoblot analysis with antibodies specific to 15(S)-lipoxygenase-1 (LOX-1) and 15(S)-lipoxygenase-2 (LOX-2) demonstrated the expression of 15-LOX-2, but not 15-LOX-1, in these tumor cells [6].
15-Lipoxygenase 2 (15-LOX2), the most abundant arachidonate (AA)-metabolizing enzyme expressed in adult human prostate, is a negative cell-cycle regulator in normal human prostate epithelial cells [7].

Chemical compound and disease context of ALOX15B

In the current study, we have characterized the distribution of 15-LOX-2 in the human prostate by immunohistochemistry, demonstrated the ability of benign prostate tissue to form 15S-hydroxyeicosatetraenoic acid (15S-HETE) from exogenous arachidonic acid (AA), and begun characterizing possible alterations in 15-LOX-2 in prostate adenocarcinoma [8].

Biological context of ALOX15B

ALOX15B is located in the same orientation 25 kb downstream of ALOX12B, and is composed of 14 exons and 13 introns spanning a total of 9.7 kb of genomic sequence [9].
Addition of PPAR-gamma ligand 15-hydroxyeicosatetraenoic acid in the presence of PPAR-gamma expression caused further down-regulation of 15-lipoxygenase-2 [10].
Inverse relationship between 15-lipoxygenase-2 and PPAR-gamma gene expression in normal epithelia compared with tumor epithelia [11].
Taken together, these results suggest that 15-LOX2 could be a suppressor of prostate cancer development, which functions by restricting cell cycle progression [12].
Site-directed mutagenesis reveals that this putative NLS is only partially involved in the nuclear import of 15-LOX2 [7].

Anatomical context of ALOX15B

Normal epithelial cells/samples generally expressed high levels of 15-LOX-2 along with the enzyme product 15-S-HETE, but both levels were reduced in cancer cells/samples [11].
Western blotting with multiple primary prostate cell strains and prostate cancer cell lines reveals that the expression of 15-LOX2 is lost in all prostate cancer cell lines, accompanied by decreased enzymatic activity revealed by liquid chromatography/tandem mass spectrometry analyses [12].
Immunocytochemistry and biochemical fractionation reveal that 15-LOX2 is expressed at multiple subcellular locations, including cytoplasm, cytoskeleton, cell-cell border, and nucleus [7].
15-Lipoxygenase-2 expression in benign and neoplastic sebaceous glands and other cutaneous adnexa [3].
Strong 15-lipoxygenase-2 immunostaining was also observed in secretory cells of apocrine and eccrine glands [3].

Associations of ALOX15B with chemical compounds

Together, these results suggest that both 15-LOX2 and 15-LOX2sv-b suppress prostate tumor development, and the tumor-suppressive functions apparently do not necessarily depend on AA-metabolizing activity and nuclear localization [7].
The results indicate that androgen does not directly regulate 15-LOX2 gene expression [13].
We identified an active steroid nuclear receptor half-site present in the 15-LOX-2 promoter fragment F-5 (-618/+177) that can interact with PPARgamma [14].
Soybean 15-LOX, rabbit reticulocyte 15-LOX, human 15-LOX-1, and human 15-LOX-2 oxygenate 2-AG, providing 15(S)-hydroperoxyeicosatetraenoic acid glyceryl ester [15].

Physical interactions of ALOX15B

Peroxisome proliferator-activated receptor gamma interacted with 15-LOX-2 promoter sequences in pulldown experiments using biotinylated 15-LOX-2 (-560/-596 bp) oligonucleotides [14].

Other interactions of ALOX15B

15-Lipoxygenase-2, expressed at high levels in ECs, was down-regulated by transfecting PPAR-gamma expression construct (either gamma1 or gamma2 isoform) into ECs [10].
To determine whether this mechanism is applicable to prostate cancer and what the effects of 15-LOX-2 are, we investigated the effect of 15-LOX-1, 15-LOX-2, and their metabolites on epidermal growth factor (EGF)- and insulin-like growth factor (IGF)-1 signaling in prostate carcinoma cells [2].
Since 15-LOX2 is normally expressed in the prostate luminal epithelial cells, we subsequently explored whether androgen/androgen receptor may directly regulate its gene expression [13].
In this project, we studied the gene regulation of 15-lipoxygenase 2 (15-LOX2), the most abundant arachidonate-metabolizing LOX in adult human prostate and a negative cell-cycle regulator in normal human prostate (NHP) epithelial cells [13].
A significant inverse correlation was also noted between 15-LOX-2 immunostaining and tumor cell proliferation (Ki-67 immunostaining; P < 0.0001) [16].

Analytical, diagnostic and therapeutic context of ALOX15B

Strong uniform 15-lipoxygenase-2 in situ hybridization (n = 6) and immunostaining (n = 16) were observed in benign cutaneous sebaceous glands, with expression in differentiated secretory cells [3].
Immunostaining of 18 radical prostatectomy specimens showed a loss of 15-LOX-2 in the majority of prostate adenocarcinomas; 14 of 18 cases showed loss of 15-LOX-2 in >25% of the tumor (mean, 74.9% negative for 15-LOX-2; range, 38.9% to 100%) [8].
15-LOX-2 but not 15-LOX-1 was detected by Western blot analysis, although we were able to detect similar levels of both 15-LOX mRNAs by real-time quantitative RT-PCR [17].
In peripheral zone tumors without complete loss of 15-LOX-2 expression, there was a significant inverse relationship between 15-LOX-2 immunostaining and tumor volume [18].

References

The critical role of 15-lipoxygenase-1 in colorectal epithelial cell terminal differentiation and tumorigenesis. Shureiqi, I., Wu, Y., Chen, D., Yang, X.L., Guan, B., Morris, J.S., Yang, P., Newman, R.A., Broaddus, R., Hamilton, S.R., Lynch, P., Levin, B., Fischer, S.M., Lippman, S.M. Cancer Res. (2005) [Pubmed]
Opposing effects of 15-lipoxygenase-1 and -2 metabolites on MAPK signaling in prostate. Alteration in peroxisome proliferator-activated receptor gamma. Hsi, L.C., Wilson, L.C., Eling, T.E. J. Biol. Chem. (2002) [Pubmed]
15-Lipoxygenase-2 expression in benign and neoplastic sebaceous glands and other cutaneous adnexa. Shappell, S.B., Keeney, D.S., Zhang, J., Page, R., Olson, S.J., Brash, A.R. J. Invest. Dermatol. (2001) [Pubmed]
Reduced 15S-lipoxygenase-2 expression in esophageal cancer specimens and cells and upregulation in vitro by the cyclooxygenase-2 inhibitor, NS398. Xu, X.C., Shappell, S.B., Liang, Z., Song, S., Menter, D., Subbarayan, V., Iyengar, S., Tang, D.G., Lippman, S.M. Neoplasia (2003) [Pubmed]
15S-Hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor gamma and inhibits proliferation in PC3 prostate carcinoma cells. Shappell, S.B., Gupta, R.A., Manning, S., Whitehead, R., Boeglin, W.E., Schneider, C., Case, T., Price, J., Jack, G.S., Wheeler, T.M., Matusik, R.J., Brash, A.R., Dubois, R.N. Cancer Res. (2001) [Pubmed]
15S-Lipoxygenase-2 mediates arachidonic acid-stimulated adhesion of human breast carcinoma cells through the activation of TAK1, MKK6, and p38 MAPK. Nony, P.A., Kennett, S.B., Glasgow, W.C., Olden, K., Roberts, J.D. J. Biol. Chem. (2005) [Pubmed]
Subcellular localization and tumor-suppressive functions of 15-lipoxygenase 2 (15-LOX2) and its splice variants. Bhatia, B., Maldonado, C.J., Tang, S., Chandra, D., Klein, R.D., Chopra, D., Shappell, S.B., Yang, P., Newman, R.A., Tang, D.G. J. Biol. Chem. (2003) [Pubmed]
15-lipoxygenase-2 (15-LOX-2) is expressed in benign prostatic epithelium and reduced in prostate adenocarcinoma. Shappell, S.B., Boeglin, W.E., Olson, S.J., Kasper, S., Brash, A.R. Am. J. Pathol. (1999) [Pubmed]
A gene cluster encoding human epidermis-type lipoxygenases at chromosome 17p13.1: cloning, physical mapping, and expression. Krieg, P., Marks, F., Fürstenberger, G. Genomics (2001) [Pubmed]
Differential peroxisome proliferator-activated receptor-gamma isoform expression and agonist effects in normal and malignant prostate cells. Subbarayan, V., Sabichi, A.L., Kim, J., Llansa, N., Logothetis, C.J., Lippman, S.M., Menter, D.G. Cancer Epidemiol. Biomarkers Prev. (2004) [Pubmed]
Inverse relationship between 15-lipoxygenase-2 and PPAR-gamma gene expression in normal epithelia compared with tumor epithelia. Subbarayan, V., Xu, X.C., Kim, J., Yang, P., Hoque, A., Sabichi, A.L., Llansa, N., Mendoza, G., Logothetis, C.J., Newman, R.A., Lippman, S.M., Menter, D.G. Neoplasia (2005) [Pubmed]
Evidence that arachidonate 15-lipoxygenase 2 is a negative cell cycle regulator in normal prostate epithelial cells. Tang, S., Bhatia, B., Maldonado, C.J., Yang, P., Newman, R.A., Liu, J., Chandra, D., Traag, J., Klein, R.D., Fischer, S.M., Chopra, D., Shen, J., Zhau, H.E., Chung, L.W., Tang, D.G. J. Biol. Chem. (2002) [Pubmed]
Evidence that Sp1 positively and Sp3 negatively regulate and androgen does not directly regulate functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) gene expression in normal human prostate epithelial cells. Tang, S., Bhatia, B., Zhou, J., Maldonado, C.J., Chandra, D., Kim, E., Fischer, S.M., Butler, A.P., Friedman, S.L., Tang, D.G. Oncogene (2004) [Pubmed]
15-Lipoxygenase-2 gene regulation by its product 15-(S)-hydroxyeicosatetraenoic acid through a negative feedback mechanism that involves peroxisome proliferator-activated receptor gamma. Subbarayan, V., Krieg, P., Hsi, L.C., Kim, J., Yang, P., Sabichi, A.L., Llansa, N., Mendoza, G., Logothetis, C.J., Newman, R.A., Lippman, S.M., Menter, D.G. Oncogene (2006) [Pubmed]
15-Lipoxygenase metabolism of 2-arachidonylglycerol. Generation of a peroxisome proliferator-activated receptor alpha agonist. Kozak, K.R., Gupta, R.A., Moody, J.S., Ji, C., Boeglin, W.E., DuBois, R.N., Brash, A.R., Marnett, L.J. J. Biol. Chem. (2002) [Pubmed]
15-Lipoxygenase-2 expression in benign and neoplastic lung: an immunohistochemical study and correlation with tumor grade and proliferation. Gonzalez, A.L., Roberts, R.L., Massion, P.P., Olson, S.J., Shyr, Y., Shappell, S.B. Hum. Pathol. (2004) [Pubmed]
Detection and subcellular localization of two 15S-lipoxygenases in human cornea. Chang, M.S., Schneider, C., Roberts, R.L., Shappell, S.B., Haselton, F.R., Boeglin, W.E., Brash, A.R. Invest. Ophthalmol. Vis. Sci. (2005) [Pubmed]
Reduced 15-lipoxygenase-2 immunostaining in prostate adenocarcinoma: correlation with grade and expression in high-grade prostatic intraepithelial neoplasia. Jack, G.S., Brash, A.R., Olson, S.J., Manning, S., Coffey, C.S., Smith, J.A., Shappell, S.B. Hum. Pathol. (2000) [Pubmed]

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