scholarly journals Lack of whey acidic protein (WAP) four-disulfide core domain protease inhibitor 2 (WFDC2) causes neonatal death from respiratory failure in mice

2019 ◽  
Vol 12 (11) ◽  
pp. dmm040139 ◽  
Author(s):  
Kuniko Nakajima ◽  
Michio Ono ◽  
Uroš Radović ◽  
Selma Dizdarević ◽  
Shin-ichi Tomizawa ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Protease Inhibitor ◽  
Neonatal Death ◽  
Whey Acidic Protein ◽  
Acidic Protein ◽  
Core Domain

scholarly journals A locus on human chromosome 20 contains several genes expressing protease inhibitor domains with homology to whey acidic protein

2002 ◽  
Vol 368 (1) ◽  
pp. 233-242 ◽  
Author(s):  
Adam CLAUSS ◽  
Hans LILJA ◽  
Åke LUNDWALL
Keyword(s):  
Human Chromosome ◽  
Protease Inhibitor ◽  
Proteolytic Enzymes ◽  
Whey Acidic Protein ◽  
Acidic Protein ◽  
Promoter Regions ◽  
Transcript Levels ◽  
Genes Encoding ◽  
Characteristic Features ◽  
Rapid Amplification

A locus containing 14 genes, encoding protein domains that have homology with whey acidic protein (WAP), has been identified in a region of 678kb on human chromosome 20q12-13.1. Among them are genes of the known or postulated protease inhibitors elafin, secretory leucocyte protease inhibitor, human epididymis gene product 4, eppin, and huWAP2. Nucleotide sequences of full-length transcripts were obtained from cDNA fragments generated by rapid amplification of cDNA ends. Characteristic features of the genes are that the upstream promoter regions are devoid of TATA-boxes and that the coding nucleotides are divided into distinct exons for the signal peptide and for each WAP domain. In most cases, there is also a separate exon encompassing a few terminal codons and the 3′ untranslated nucleotides. There are also examples of mixed type inhibitors, that encode inhibitor domains of both WAP and Kunitz types. Several of the genes appear to be expressed ubiquitously, but, in most cases, the highest transcript levels are found in epididymis followed by testis and trachea. Some of the genes also display high transcript levels in neural tissues. Potential biological roles of protein products could be in host defence against invading micro-organisms or in the regulation of endogenous proteolytic enzymes, of which those originating from the kallikrein gene locus on chromosome 19 are of particular interest.

scholarly journals Decreased IGF Type 1 Receptor Signaling in Mammary Epithelium during Pregnancy Leads to Reduced Proliferation, Alveolar Differentiation, and Expression of Insulin Receptor Substrate (IRS)-1 and IRS-2

Endocrinology ◽  
2011 ◽  
Vol 152 (8) ◽  
pp. 3233-3245 ◽  
Author(s):  
Zhaoyu Sun ◽  
Sain Shushanov ◽  
Derek LeRoith ◽  
Teresa L. Wood
Keyword(s):  
Insulin Receptor ◽  
Mammary Epithelium ◽  
Whey Acidic Protein ◽  
Dominant Negative ◽  
Acidic Protein ◽  
Normal Mammary Gland ◽  
Insulin Receptor Substrate ◽  
Alveolar Development ◽  
Pregnancy And Lactation

The IGFs and the IGF type 1 receptor (IGF-1R) are essential mediators of normal mammary gland development in mice. IGF-I and the IGF-1R have demonstrated functions in formation and proliferation of terminal end buds and in ductal outgrowth and branching during puberty. To study the functions of IGF-1R during pregnancy and lactation, we established transgenic mouse lines expressing a human dominant-negative kinase dead IGF-1R (dnhIGF-1R) under the control of the whey acidic protein promoter. We provide evidence that the IGF-1R pathway is necessary for normal epithelial proliferation and alveolar formation during pregnancy. Furthermore, we demonstrate that the whey acidic protein-dnhIGF-1R transgene causes a delay in alveolar differentiation including lipid droplet formation, lumen expansion, and β-casein protein expression. Analysis of IGF-1R signaling pathways showed a decrease in P-IGF-1R and P-Akt resulting from expression of the dnhIGF-1R. We further demonstrate that disruption of the IGF-1R decreases mammary epithelial cell expression of the signaling intermediates insulin receptor substrate (IRS)-1 and IRS-2. No alterations were observed in downstream signaling targets of prolactin and progesterone, suggesting that activation of the IGF-1R may directly regulate expression of IRS-1/2 during alveolar development and differentiation. These data show that IGF-1R signaling is necessary for normal alveolar proliferation and differentiation, in part, through induction of signaling intermediates that mediate alveolar development.

scholarly journals The effect of whey acidic protein fractions on bone loss in the ovariectomised rat

2005 ◽  
Vol 94 (2) ◽  
pp. 244-252 ◽  
Author(s):  
Marlena C. Kruger ◽  
Gabrielle G. Plimmer ◽  
Linda M. Schollum ◽  
Neill Haggarty ◽  
Satyendra Ram ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Loss ◽  
Bovine Milk ◽  
Whey Acidic Protein ◽  
Acidic Protein ◽  
Protein Fractions ◽  
Female Rats ◽  
Mineral Density ◽  
Milk Whey ◽  
Over Time

Bovine milk has been shown to contain bioactive components with bone-protective properties. Earlier studies on bovine milk whey protein showed that it suppressed bone resorption in the female ovariectomised rat. A new osteotropic component was subsequently identified in the whey basic protein fraction, but bone bioactivity may also be associated with other whey fractions. In the present study, we investigated whether acidic protein fractions isolated from bovine milk whey could prevent bone loss in mature ovariectomised female rats. Six-month-old female rats were ovariectomised (OVX) or left intact (sham). The OVX rats were randomised into four groups. One group remained the control (OVX), whereas three groups were fed various whey acidic protein fractions from milk whey as 3g/kg diet for 4 months. Outcomes were bone mineral density, bone biomechanics and markers of bone turnover. Bone mineral density of the femurs indicated that one of the whey AF over time caused a recovery of bone lost from OVX. Plasma C-telopeptide of type I collagen decreased significantly in all groups except OVX control over time, indicating an anti-resorptive effect of whey acidic protein. Biomechanical data showed that the AF may affect bone architecture as elasticity was increased by one of the whey AF. The femurs of AF-supplemented rats all showed an increase in organic matter. This is the first report of an acidic whey protein fraction isolated from milk whey that may support the recovery of bone loss in vivo.

The effect of low-to-moderate-dose ethanol consumption on rat mammary gland structure and function and early postnatal growth of offspring

2013 ◽  
Vol 304 (10) ◽  
pp. R791-R798 ◽  
Author(s):  
Megan E. Probyn ◽  
Emma-Kate Lock ◽  
Stephen T. Anderson ◽  
Sarah Walton ◽  
John F. Bertram ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Alcohol Consumption ◽  
Milk Proteins ◽  
Postnatal Growth ◽  
Whey Acidic Protein ◽  
Acidic Protein ◽  
Postnatal Life ◽  
Sprague Dawley ◽  
Moderate Dose ◽  
Protein Levels

High levels of alcohol consumption during pregnancy can lead to growth deficits in early postnatal life. However, the effects of low-to-moderate alcohol consumption during pregnancy are less clearly defined. The aim of this study was to determine whether low-to-moderate ethanol (EtOH) consumption throughout pregnancy in the rat alters maternal mammary gland morphology and milk protein levels, thereby affecting lactation and the growth of pups after birth. Sprague-Dawley rats were fed an ad libitum liquid diet ± 6% vol/vol EtOH throughout pregnancy. Mammary glands from dams were collected at embryonic day (E) 20 or postnatal day (PN) 1, and expression of milk proteins (α-lactalbumin, β-casein, and whey acidic protein) was examined. In addition, relative amounts of alveoli, lactiferous ducts, adipose tissue, and blood vessels were determined at PN1. A subset of rats gave birth, and offspring growth and milk intake were recorded. Mammary gland weight was unaltered by EtOH, and stereological analysis showed no differences in gland structure compared with control. Although there were no significant changes in mammary gland gene expression at the RNA level, protein levels of α-lactalbumin were increased and whey acidic protein were decreased by EtOH. Offspring of EtOH-fed dams consumed less milk than controls in the lactational period; however, this did not alter their early postnatal growth. Overall, it appears that low-to-moderate-dose prenatal EtOH exposure does not significantly alter mammary gland development but may alter the composition of the various proteins found within the milk in a manner that maintains overall pup growth.

scholarly journals Analysis of the Promoter of Mutated Human Whey Acidic Protein (WAP) Gene

2006 ◽  
Vol 52 (2) ◽  
pp. 315-320 ◽  
Author(s):  
Naoko NUKUMI ◽  
Mami SEKI ◽  
Tokuko IWAMORI ◽  
Tetsushi YADA ◽  
Kunihiko NAITO ◽  
...  
Keyword(s):  
Whey Acidic Protein ◽  
Acidic Protein

scholarly journals Whey Acidic Protein (WAP) Depresses the Proliferation of Mouse (MMT) and Human (MCF-7) Mammary Tumor Cells

2005 ◽  
Vol 51 (5) ◽  
pp. 649-656 ◽  
Author(s):  
Naoko NUKUMI ◽  
Tokuko IWAMORI ◽  
Kunihiko NAITO ◽  
Hideaki TOJO
Keyword(s):  
Tumor Cells ◽  
Mammary Tumor ◽  
Whey Acidic Protein ◽  
Acidic Protein ◽  
Mammary Tumor Cells ◽  
Mcf 7

A distal region, hypersensitive to DNase I, plays a key role in regulating rabbit whey acidic protein gene expression

2001 ◽  
Vol 359 (3) ◽  
pp. 557-565 ◽  
Author(s):  
Benjamin MILLOT ◽  
Marie-Louise FONTAINE ◽  
Dominique THEPOT ◽  
Eve DEVINOY
Keyword(s):  
Mammary Gland ◽  
Sequence Similarity ◽  
Distal Region ◽  
Dnase I ◽  
Whey Acidic Protein ◽  
Acidic Protein ◽  
Upstream Region ◽  
Lactating Mammary Gland

The aim of the present study was to identify the functional domains of the upstream region of the rabbit whey acidic protein (WAP) gene, which has been used with considerable efficacy to target the expression of several foreign genes to the mammary gland. We have shown that this region exhibits three sites hypersensitive to DNase I digestion in the lactating mammary gland, and that all three sites harbour elements which can bind to Stat5 in vitro in bandshift assays. However, not all hypersensitive regions are detected at all stages from pregnancy to weaning, and the level of activated Stat5 detected in the rabbit mammary gland is low except during lactation. We have studied the role of the distal site, which is only detected during lactation, in further detail. It is located within a 849bp region that is required to induce a strong expression of the chloramphenicol acetyltransferase reporter gene in transfected mammary cells. Taken together, these results suggest that this region, centred around a Stat5-binding site and surrounded by a variable chromatin structure during the pregnancy–lactation cycle, may play a key role in regulating the expression of this gene in vivo. Furthermore, this distal region exhibits sequence similarity with a region located around 3kb upstream of the mouse WAP gene. The existence of such a distal region in the mouse WAP gene may explain the differences in expression between 4.1 and 2.1kb mouse WAP constructs.

scholarly journals Complete sequence of the rabbit whey acidic protein gene

1990 ◽  
Vol 18 (12) ◽  
pp. 3641-3641 ◽  
Author(s):  
D. Thepot ◽  
E. Devinoy ◽  
M.L. Fontaine ◽  
C. Hubert ◽  
L.M. Houdebine
Keyword(s):  
Protein Gene ◽  
Complete Sequence ◽  
Whey Acidic Protein ◽  
Acidic Protein

scholarly journals The role of whey acidic protein four-disulfide-core proteins in respiratory health and disease

2017 ◽  
Vol 398 (4) ◽  
pp. 425-440 ◽  
Author(s):  
Donna M. Small ◽  
Declan F. Doherty ◽  
Caoifa M. Dougan ◽  
Sinéad Weldon ◽  
Clifford C. Taggart
Keyword(s):  
Protein Function ◽  
Respiratory Health ◽  
Whey Acidic Protein ◽  
Acidic Protein ◽  
Current Evidence ◽  
Core Proteins ◽  
Health And Disease ◽  
Low Molecular Weight Proteins ◽  
Potential Therapeutics

Abstract Members of the whey acidic protein (WAP) or WAP four-disulfide-core (WFDC) family of proteins are a relatively under-explored family of low molecular weight proteins. The two most prominent WFDC proteins, secretory leukocyte protease inhibitor (SLPI) and elafin (or the precursor, trappin-2), have been shown to possess multiple functions including anti-protease, anti-bacterial, anti-viral and anti-inflammatory properties. It is therefore of no surprise that both SLPI and elafin/trappin-2 have been developed as potential therapeutics. Given the abundance of SLPI and elafin/trappin-2 in the human lung, most work in the area of WFDC research has focused on the role of WFDC proteins in protecting the lung from proteolytic attack. In this review, we will outline the current evidence regarding the expanding role of WFDC protein function with a focus on WFDC activity in lung disease as well as emerging data regarding the function of some of the more recently described WFDC proteins.

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