The role of the IGF system in mammary physiology of ruminants.

The IGF system plays a central role in all stages of mammary development, lactation and involution. IGFs exert their effects on the mammary gland through both endocrine and paracrine/autocrine mechanisms and the importance of circulating versus local IGF action remains an open question, especially in ruminants. At the whole organ level, a critical role for IGFs in ductal morphogenesis and lobuloalveolar development has been established, while at the cellular level the ability of IGFs to stimulate cell proliferation and control cell survival contributes to the number of milk-secreting cells in the gland.

Testosterone Reduces Growth and Hepatic mRNA in a Female-Larger Lizard, : Evidence of an Evolutionary Reversal in Growth Regulation.

Previous research has demonstrated that testosterone (T) can inhibit growth in female-larger species and stimulate growth in male-larger species, but the underlying mechanisms of this regulatory bipotentiality have not been investigated. In this study, we investigated the effects of T on the expression of hepatic insulin-like growth factor-1 () mRNA and circulating IGF-1 hormone in , a species of lizard in which females grow faster to become larger than males and in which T inhibits growth. Experiments were performed in captivity on mature female and male adults in the asymptotic phase of their growth curve and on actively growing, pre-reproductive juveniles.

Fetal Alcohol Exposure Alters Mammary Epithelial Cell Subpopulations and Promotes Tumorigenesis.

Background: Fetal alcohol exposure (FAE) increases the risk of mammary tumorigenesis in adult offspring; however, the underlying mechanism remains unknown. This study tested the hypothesis that FAE shifts the mammary epithelial cell (MEC) composition toward one that promotes tumorigenesis.

Methods: Pregnant Friend Virus B NIH Jackson dams bred to MMTV-Wnt1 male mice were given ad libitum access to 5% alcohol in 0.

IGFBP-3 Induced by Ribotoxic Stress Traffics From the Endoplasmic Reticulum to the Nucleus in Mammary Epithelial Cells.

IGF-binding protein (IGFBP)-3 is a multifunctional protein that can exert IGF-independent effects on apoptosis. Anisomycin (ANS) is a potent inducer of IGFBP-3 production in bovine mammary epithelial cells (MECs), and knockdown of IGFBP-3 attenuates ANS-induced apoptosis. IGFBP-3 is present in the nucleus and the conditioned media in response to ANS.

Paul D. Sturkie: Avian cardiac physiologist.

Sturkie's Avian Physiology is a highly regarded textbook for the study of comparative poultry physiology. Less well known, however, is the contribution of Paul D. Sturkie (1909-2002) as a pioneer in the experimental physiology of avian species.

Toxicity of ricin A chain is reduced in mammalian cells by inhibiting its interaction with the ribosome.

Ricin is a potent ribotoxin that is considered a bioterror threat due to its ease of isolation and possibility of aerosolization. In yeast, mutation of arginine residues away from the active site results in a ricin toxin A chain (RTA) variant that is unable to bind the ribosome and exhibits reduced cytotoxicity. The goal of the present work was to determine if these residues contribute to ribosome binding and cytotoxicity of RTA in mammalian cells.

Peroral Estradiol Is Sufficient to Induce Carcinogen-Induced Mammary Tumorigenesis in Ovariectomized Rats without Progesterone.

A role for estrogens in breast cancer is widely accepted, however, recent evidence highlights that timing and exposure levels are important in determining whether they elicit harmful versus beneficial effects. The rat chemical carcinogen model has been widely used to study the effects of estrogens but conclusions on the levels that lead to tumor development and an absolute requirement for progesterone (P4) are lacking. A newer method of hormone administration mixes hormones with nut butter for peroral consumption allowing for a less stressful method of long-term administration with lower spikes in serum estradiol (E2) levels.

Tumor Phenotype and Gene Expression During Early Mammary Tumor Development in Offspring Exposed to Alcohol In Utero.

Background: Alcohol exposure in utero increases susceptibility to carcinogen-induced mammary tumorigenesis in adult offspring and causes tumors with a more malignant phenotype. This study was conducted to identify changes early in tumor development that might lead to this outcome.

Methods: Pregnant Sprague-Dawley rats were fed a liquid diet containing 6.

Endogenous IGFBP-3 Mediates Intrinsic Apoptosis Through Modulation of Nur77 Phosphorylation and Nuclear Export.

In nontransformed bovine mammary epithelial cells, the intrinsic apoptosis inducer anisomycin (ANS) induces IGFBP-3 expression and nuclear localization and knockdown of IGFBP-3 attenuates ANS-induced apoptosis. Others have shown in prostate cancer cells that exogenous IGFBP-3 induces apoptosis by facilitating nuclear export of the orphan nuclear receptor Nur77 and its binding partner, retinoid X receptor-α (RXRα). The goal of the present work was to determine whether endogenous IGFBP-3 plays a role in ANS-induced apoptosis by facilitating nuclear transport of Nur77 and/or RXRα in nontransformed cells.

Nutritional modulation of IGF-1 in relation to growth and body condition in Sceloporus lizards.

Nutrition and energy balance are important regulators of growth and the growth hormone/insulin-like growth factor (GH/IGF) axis. However, our understanding of these functions does not extend uniformly to all classes of vertebrates and is mainly limited to controlled laboratory conditions. Lizards can be useful models to improve our understanding of the nutritional regulation of the GH/IGF-1 axis because many species are relatively easy to observe and manipulate both in the laboratory and in the field.

Fetal alcohol exposure and mammary tumorigenesis in offspring: role of the estrogen and insulin-like growth factor systems.

Fetal alcohol spectrum disorders affect a significant number of live births each year, indicating that alcohol consumption during pregnancy is an important public health issue. Environmental exposures and lifestyle choices during pregnancy may affect the offspring's risk of disease in adulthood, leading to the idea that a woman's risk of breast cancer may be pre-programmed prior to birth. Exposure of pregnant rats to alcohol increases tumorigenesis in the adult offspring in response to mammary carcinogens.

A relatively low level of ribosome depurination by mutant forms of ricin toxin A chain can trigger protein synthesis inhibition, cell signaling and apoptosis in mammalian cells.

The A chain of the plant toxin ricin (RTA) is an N-glycosidase that inhibits protein synthesis by removing a specific adenine from the 28S rRNA. RTA also induces ribotoxic stress, which activates stress-induced cell signaling cascades and apoptosis. However, the mechanistic relationship between depurination, protein synthesis inhibition and apoptosis remains an open question.

IGF binding protein-3 mediates stress-induced apoptosis in non-transformed mammary epithelial cells.

Mammary epithelial cell (MEC) number is an important determinant of milk production in lactating dairy cows. IGF-I increases IGF binding protein-3 (IGFBP-3) production in these cells, which plays a role in its ability to enhance proliferation. In the present study, we show that the apoptotic factor anisomycin (ANS) also increases IGFBP-3 mRNA and protein in a dose- and concentration-dependent manner that mirrors activation of caspase-3 and -7, with significant increases in both IGFBP-3 protein and caspase activation observed by 3 h.

Inhibition of the unfolded protein response by ricin a-chain enhances its cytotoxicity in mammalian cells.

Ricin is a highly toxic type II ribosome-inactivating protein that has potential as a biochemical weapon and as the toxic component of immunotoxins. The unfolded protein response (UPR) is a survival response that helps cells to recover from endoplasmic reticulum (ER) stress. Failure to recover from ER stress leads to apoptosis.

Alcohol exposure in utero leads to enhanced prepubertal mammary development and alterations in mammary IGF and estradiol systems.

Exposure to alcohol during fetal development increases susceptibility to mammary cancer in adult rats. This study determined if early changes in mammary morphology and the insulin-like growth factor (IGF)/estradiol axis are involved in the mechanisms that underlie this increased susceptibility. Pregnant Sprague-Dawley rats were fed a liquid diet containing 6.

Fetal alcohol exposure increases mammary tumor susceptibility and alters tumor phenotype in rats.

Background: Altered fetal programming because of a suboptimal in utero environment has been shown to increase susceptibility to many diseases later in life. This study examined the effect of alcohol exposure in utero on N-nitroso-N-methylurea (NMU)-induced mammary cancer risk during adulthood.

Methods: Study 1: Pregnant Sprague Dawley rats were fed a liquid diet containing 6.

Ricin A-chain requires c-Jun N-terminal kinase to induce apoptosis in nontransformed epithelial cells.

Ricin is a toxin isolated from castor beans that has potential as a weapon of bioterrorism. This glycoprotein consists of an A-chain (RTA) that damages the ribosome and inhibits protein synthesis and a B-chain that plays a role in cellular uptake. Ricin activates the c-Jun N-terminal kinase (JNK) and p38 signaling pathways; however, a role for these pathways in ricin-induced cell death has not been investigated.

Endogenous IGFBP-3 is required for both growth factor-stimulated cell proliferation and cytokine-induced apoptosis in mammary epithelial cells.

TNF-alpha and IGF-I exert opposing effects on mammary epithelial cell (MEC) growth and survival. However, both increase IGF binding protein-3 (IGFBP-3) expression, a multifunctional protein that plays both IGF-dependent as well as independent roles in these processes. We have reported that IGF-I utilizes the PI3-K and MAPK pathways to induce IGFBP-3 expression in bovine MEC.

The mitogen-activated protein kinase pathway tonically inhibits both basal and IGF-I-stimulated IGF-binding protein-5 production in mammary epithelial cells.

The IGF system plays a key role in mammary gland growth and development. Our lab previously reported that IGF-I primarily regulates IGF-binding protein (BP)-3 in bovine mammary epithelial cells (MEC) and IGFBP-5 in mammary fibroblasts (MF). Presently, we examined the signaling pathways used by IGF-I to elicit this distinct, cell-type specific regulation.

Insulin growth factor-I and epidermal growth factor receptors recruit distinct upstream signaling molecules to enhance AKT activation in mammary epithelial cells.

IGF-I and epidermal growth factor (EGF) stimulate both normal mammary epithelial cell (MEC) growth and tumorigenesis. Whereas both growth factors increase DNA synthesis in MECs, how they evoke a greater response in combination when they activate similar signaling pathways remains unknown. In the present study, we investigated the signaling pathways by which these mitogens act in concert to increase DNA synthesis.

Stimulation of insulin-like growth factor (IGF) binding protein-3 synthesis by IGF-I and transforming growth factor-alpha is mediated by both phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways in mammary epithelial cells.

IGF binding protein (IGFBP)-3 is an important regulator of mammary epithelial cell (MEC) growth and can enhance the ability of both IGF-I and epidermal growth factor ligands such as TGFalpha to stimulate MEC proliferation. Here we investigate the role of the phosphatidylinositol-3 kinase (PI3K) and MAPK pathways in the regulation of IGFBP-3 expression by IGF-I and TGFalpha in bovine MECs. Both growth factors stimulated DNA synthesis, although IGF-I was the stronger mitogen.