Purification of alpha-fetoprotein from human cord serum with demonstration of its antiestrogenic activity

Allen, S.H.G.; Bennett, James A.; Mizejewski, Gerald J.; Andersen, Thomas T.; Ferraris, Suellen P.; Jacobson, Herbert I.

doi:10.1016/0167-4838(93)90074-2

Cited by 26 publications

(12 citation statements)

References 15 publications

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“…Conversely, lower levels of estrogens during pregnancy seem to decrease breast cancer risk. Maternal levels of circulating alpha‐fetoprotein, a glycoprotein that binds to estrogen and suppresses its activity 87,88 during pregnancy, are inversely associated with breast cancer risk 89,90 . Furthermore, women who suffered from pre‐eclampsia and pregnancy hypertension are at reduced risk of developing breast cancer 78,91 .…”

Section: Why Does Timing Of Estrogenic/dietary Exposures Determine Thmentioning

confidence: 99%

Timing of Dietary Estrogenic Exposures and Breast Cancer Risk

Assis

Hilakivi‐Clarke

2006

Annals of the New York Academy of Sciences

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The same dietary component, such as fat or phytochemicals in plant foods, can have an opposite effect on breast cancer risk if exposed in utero through a pregnant mother or at puberty. Dietary exposures during pregnancy often have similar effects on breast cancer risk among mothers and their female offspring. High fat intake and obesity are illustrative examples: excessive pregnancy weight gain that increases high birth weight is associated with increased breast cancer risk among mothers and daughters. High body weight during childhood is inversely linked to later breast cancer risk. The main reason why the age when dietary exposures occur determines their effect on breast cancer risk likely reflects the extensive programming of the mammary gland during fetal life and subsequent reprogramming at puberty and pregnancy. Programming is a series of epigenetic/transcriptional modifications in gene expression that can be influenced by changes in the hormonal environment induced, for example, by diet. Because epigenetic modifications are inherited by daughter cells, they can persist throughout life if they occur in mammary stem cells or uncommitted mammary myoepithelial or luminal progenitor cells. Our results indicate that the estrogen receptor (ER), mitogen-activated protein kinase (MAPK), and the tumor suppressors BRCA1, p53, and caveolin-1 are among the genes affected by diet-induced alterations in programming/reprogramming. Consequently, mammary gland morphology may be altered in a manner that increases or reduces susceptibility to malignant transformation, including an increase/reduction in cell proliferation, differentiation, and survival, or in the number of terminal end buds (TEBs) or pregnancy-induced mammary epithelial cells (PI-MECs) that are the sites where breast cancer is initiated. Thus, dietary exposures during pregnancy and puberty may play an important role in determining later risk by inducing epigenetic changes that modify vulnerability to breast cancer.

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Section: Why Does Timing Of Estrogenic/dietary Exposures Determine Thmentioning

confidence: 99%

Timing of Dietary Estrogenic Exposures and Breast Cancer Risk

Assis

Hilakivi‐Clarke

2006

Annals of the New York Academy of Sciences

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“…The authors concluded that AFP was a specific inhibitor of the multiplication of cells that were E2 sensitive for growth. Because of such reports, the author of this atlas chapter undertook a series of studies to investigate and hopefully elucidate the E2-sensitive growth inhibitory properties of AFP in vivo (Mizejewski et al, 1983(Mizejewski et al, , 1986Mizejewski and Warner, 1989;Jacobson et al, 1990a;Mizejewski et al, 1990;Allen et al, 1993). These studies concluded that rodent and human AFP contained an encrypted (occult) E2-sensitive growth regulatory site that is induced to emerge following exposure to high estrogen concentrations Mizejewski et al, 1996;Vakharia and Mizejewski, 2000).…”

Section: G) Afp Peptide Sites For Hormones and Growth Factor Bindingmentioning

confidence: 99%

Mapping of Structure-Function Peptide Sites on the Human Alpha-fetoprotein Amino Acid Sequence

Mizejewski¹

2011

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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The structure of alpha-fetoprotein (AFP) is presen-ted in light of AFP membership and position in the albuminoid gene family in comparison to other gene family members. Ontogenetic AFP gene expression is reviewed considering AFP mRNA presence in various tissues at different times during development. The multiple molecular variant forms of AFP are discussed in relation to published reports of AFP binding proteins and cell surface receptors. The atlas further shows AFP as a protein consisting of multiple peptide-cassettes consisting of amino acid (AA) sequence stretches matched to peptide segments on prohormones and biological response modifier proteins. Such AFP peptide segments could potentially serve as delivery agents which could target vascular, neuroendocrine, or gastrointestinal cells. A discussion follows in which peptide epitopes, extracellular matrix proteins, serine proteases, extracellular matrix, and cellular adhesion AA identity sites on AFP are considered. The AFP molecule is also viewed as a carrier/ transport protein based on AA sequence comparison of various proteins that bind hydropho-bic ligands and heavy metals similar to AFP binding of such components. An analysis of trans-cription factors, tumor suppressors, and AA-rich motifs follows, interfaced with dimerization and nuclear localization sequence matches identified on the AFP molecule. Emphasis is further placed upon homeodomain and apoptosis AA sequence identi-ties given that AFP serves as a fetal, phasespecific protein throughout embryogenesis, histogenesis, and organogenesis. AFP AA sequences are further presented as peptide identification sites for Mapping of Structure-Function Peptide Sites on the Human Alpha-fetoprotein Amino Acid SequenceMizejewski GJ Atlas Genet Cytogenet Oncol Haematol. 2010; 14(2) 170 growth factors, receptors, cytoskeletal proteins, and chemo-kines. A closing discussion summarizes the multi-ple and varied motifs of peptide sequences matched to AAs on each of AFP's three domains. This study indicates that short peptide segments, in addition to full-length AFP, and domain and subdomain fragments of AFP, could be employed as functional agents to help unravel the complexity of biological roles ascribed to human AFP.

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“…Elevated amounts of alpha‐fetoprotein may also appear associated with tumors. Many of its properties have been investigated ( 1–19), including complex formation with unsaturated fatty acids, hormones, bilirubin, retinoic acid, metal ions, estradiol and many drugs, and in addition to transport processes alpha‐fetoprotein has other physiological functions. Unsaturated fatty acids, but not saturated fatty acids, are tightly bound to alpha‐fetoprotein and produce conformational changes in the protein, which delivers the unsaturated fatty acids to locations critical to fetal development ( 16–18).…”

mentioning

confidence: 99%

Studies on a growth‐inhibitory peptide derived from alpha‐fetoprotein and some analogs

Eisele

Mesfin

Bennett

et al. 2001

The Journal of Peptide Research

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A 34-amino acid synthetic peptide was derived from the third domain of human alpha-fetoprotein, and the peptide was shown to inhibit estrogen-stimulated growth. Under certain conditions, however, the peptide lost growth-inhibitory activity. A biophysical study of the peptide was undertaken with a goal of obtaining completely reliable preparations. The peptide was studied using gel-filtration column chromatography as a function of peptide concentration and age of solution, and was found to exhibit complex aggregation behaviors. During the early period (0-3 h) after dissolving lyophilized peptide into pH 7.4 buffer, solutions were composed mostly of trimers. At higher peptide concentrations (> or = 3.0 g/L), the trimers aggregated extensively to a large aggregate (minimum size approximately 102 peptides). At 5.0-8.0 g/L, these large aggregates increased in size (up to approximately 146 peptides) until trimers were largely exhausted from solution. During the later times (>3 h) after sample preparation, the trimeric oligomer of the peptide dissociated slowly to form dimers for samples at 0.10-3.0 g/L. After their build-up, a very small number of dimers associated to form hexamers. Disulfide bonds stabilized the dimers as indicated by the conversion of dimers to trimers upon the addition of a reducing agent, and the failure of dimers to form in the presence of reducing agent. Reducing agent did not affect trimer or large aggregate formation. Trimers were found to be active in an assay monitoring inhibition of estrogen-stimulated growth, whereas dimers and large aggregates were inactive. The two cysteines in the peptide were modified to either S-methylcysteine or S-(2-aminoethyl)cysteine, and both derivatives showed significant growth-inhibition activity. A serine analog in which both cysteines were replaced had very different aggregation behavior than the cysteine peptide and lacked its growth inhibitory ability. Peptide aggregation is critically important in establishing the ability of the peptide to inhibit growth and have anticancer activity, but the state of its two cysteines is of little influence.

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Purification of alpha-fetoprotein from human cord serum with demonstration of its antiestrogenic activity

Cited by 26 publications

References 15 publications

Timing of Dietary Estrogenic Exposures and Breast Cancer Risk

Timing of Dietary Estrogenic Exposures and Breast Cancer Risk

Mapping of Structure-Function Peptide Sites on the Human Alpha-fetoprotein Amino Acid Sequence

Studies on a growth‐inhibitory peptide derived from alpha‐fetoprotein and some analogs

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