Immunohistochemical localization of Zn-alpha 2-glycoprotein in normal human tissues.

Tada, Toyohiro; Ohkubo, Iwao; Niwa, Masanari; Sasaki, Masanori; Tateyama, Hisashi; Eimoto, Tadaaki

doi:10.1177/39.9.1918940

Cited by 136 publications

(112 citation statements)

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“…It accumulates in breast cysts, is produced by 40% of breast carcinomas, and is inducible in breast cancer cell lines by glucocorticoids and androgens (2,3). ZAG is identical in amino acid sequence to lipid-mobilizing factor that is associated with cachexia (4, 5), the wasting syndrome involving depletion of adipose and muscle tissue, such as occurs in many patients with cancer, AIDS, trypanosomiasis, and other life-threatening diseases.…”

Section: Zn-␣ 2 -Glycoprotein (Zag)mentioning

confidence: 99%

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Hydrophobic Ligand Binding by Zn-α2-glycoprotein, a Soluble Fat-depleting Factor Related to Major Histocompatibility Complex Proteins

Kennedy¹,

Heikema²,

Cooper³

et al. 2001

Journal of Biological Chemistry

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Zn-␣ 2 -glycoprotein (ZAG) is a member of the major histocompatibility complex (MHC) class I family of proteins and is identical in amino acid sequence to a tumorderived lipid-mobilizing factor associated with cachexia in cancer patients. ZAG is present in plasma and other body fluids, and its natural function, like leptin's, probably lies in lipid store homeostasis. X-ray crystallography has revealed an open groove between the helices of ZAG's ␣ 1 and ␣ 2 domains, containing an unidentified small ligand in a position similar to that of peptides in MHC proteins (Sanchez, L. M., Chirino, A. J., and Bjorkman, P. J. (1999) Science 283, 1914 -1919). Here we show, using serum-derived and bacterial recombinant protein, that ZAG binds the fluorophore-tagged fatty acid 11-(dansylamino)undecanoic acid (DAUDA) and, by competition, natural fatty acids such as arachidonic, linolenic, eicosapentaenoic, and docosahexaenoic acids. Other MHC class I-related proteins (FcRn, HFE, HLA-Cw*0702) showed no such evidence of binding. Fluorescence and isothermal calorimetry analysis showed that ZAG binds DAUDA with K d in the micromolar range, and differential scanning calorimetry showed that ligand binding increases the thermal stability of the protein. Addition of fatty acids to ZAG alters its intrinsic (tryptophan) fluorescence emission spectrum, providing a strong indication that ligand binds in the expected position close to a cluster of exposed tryptophan side chains in the groove. This study therefore shows that ZAG binds small hydrophobic ligands, that the natural ligand may be a polyunsaturated fatty acid, and provides a fluorescencebased method for investigating ZAG-ligand interactions. Zn-␣ 2 -glycoprotein (ZAG)1 is a soluble protein present in serum and other body fluids (1, 2). It accumulates in breast cysts, is produced by 40% of breast carcinomas, and is inducible in breast cancer cell lines by glucocorticoids and androgens (2,3). ZAG is identical in amino acid sequence to lipid-mobilizing factor that is associated with cachexia (4, 5), the wasting syndrome involving depletion of adipose and muscle tissue, such as occurs in many patients with cancer, AIDS, trypanosomiasis, and other life-threatening diseases. Significantly, ZAG is overexpressed in tumors that accompany fat loss, and exogenous ZAG produces cachectic symptoms in experimental animals (4, 5). ZAG, like leptin (6), therefore, participates in lipid store homeostasis, the dysregulation of which has serious implications for survival and the management of cancer and other diseases. ZAG is a member of a family of proteins typified by the class I MHC proteins (which present peptides to cytotoxic T cells) (7) and includes CD1 (which presents lipidic antigens to T cells) (8, 9), the neonatal Fc receptor (FcRn; involved in transportation of immunoglobulin across epithelia), and HFE (a transferrinbinding protein that regulates iron homeostasis) (10,11). In contrast to all other MHC-like proteins, ZAG and MIC-A (a divergent member of the MHC family) are not found in asso...

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Section: Zn-␣ 2 -Glycoprotein (Zag)mentioning

confidence: 99%

“…1 is a soluble protein present in serum and other body fluids (1,2). It accumulates in breast cysts, is produced by 40% of breast carcinomas, and is inducible in breast cancer cell lines by glucocorticoids and androgens (2,3).…”

mentioning

confidence: 99%

Hydrophobic Ligand Binding by Zn-α2-glycoprotein, a Soluble Fat-depleting Factor Related to Major Histocompatibility Complex Proteins

Kennedy¹,

Heikema²,

Cooper³

et al. 2001

Journal of Biological Chemistry

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“…15 Subsequently, ZAG was identified in secretory epithelial cells, including those of liver, breast, prostate, the gastrointestinal tract and sweat glands. 16 ZAG is overexpressed by several types of malignant tumors, such as cancers of breast, prostate, bladder and lung. [17][18][19][20] As serum ZAG levels are elevated in patients with prostate 18,21 and cervical 22 cancers, ZAG has been proposed to serve as a potential biomarker for these carcinomas.…”

Section: Introductionmentioning

confidence: 99%

Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

et al. 2010

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The importance of white adipose tissue in the control of energy balance is now firmly recognized. In addition to fuel storage, adipocytes secrete an array of proteins factors (adipokines), which regulate multiple physiological and metabolic processes as well as influence body fat accumulation. Zinc-a2-glycoprotein (ZAG), a lipid mobilizing factor initially characterized as a tumor product associated with cachexia, has recently been identified as a novel adipokine. Although the exact role of ZAG in adipose tissue remains to be clarified, there is evidence that ZAG expression appears to be inversely related to adiposity, being upregulated in cachexia whereas reduced in obesity. Investigations on the regulation of ZAG give insights into its potential function in adipose tissue with a link to lipid mobilization and an anti-inflammatory action. Recent work shows that ZAG stimulates adiponectin secretion by human adipocytes. Data from genetic studies suggest that ZAG may be a candidate gene for body weight regulation; this is supported by the demonstration that ZAG-knockout mice are susceptible to weight gain, whereas transgenic mice overexpressing ZAG exhibit weight loss. The present review summarizes these new perspectives of ZAG and the potential mechanisms by which it might modulate adipose tissue mass and function.

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“…At present, no data are available on the potential role of AZGP1 in lung cancer onset and/or progression. There is evidence that AZGP1 is present in most body fluids and in the secretory epithelial cells of many human tissues (Tada et al, 1991). AZGP1 is an adipokine that may be involved in the local regulation of adipose tissue function by stimulating lipid degradation in adipocytes; the gene is markedly upregulated in mice with cancer cachexia (Bing et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

AZGP1 mRNA levels in normal human lung tissue correlate with lung cancer disease status

et al. 2007

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Immunohistochemical localization of Zn-alpha 2-glycoprotein in normal human tissues.

Cited by 136 publications

References 4 publications

Hydrophobic Ligand Binding by Zn-α2-glycoprotein, a Soluble Fat-depleting Factor Related to Major Histocompatibility Complex Proteins

Hydrophobic Ligand Binding by Zn-α2-glycoprotein, a Soluble Fat-depleting Factor Related to Major Histocompatibility Complex Proteins

Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

AZGP1 mRNA levels in normal human lung tissue correlate with lung cancer disease status

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