Insulin receptor substrates (IRSs) are signaling adaptors that play a major role in the metabolic and mitogenic actions of insulin and insulin-like growth factors. Reports have recently noted increased levels, or activity, of IRSs in many human cancers, and some have linked this to poor patient prognosis. We found that overexpressed IRS-1 was constitutively phosphorylated in vitro and in vivo and that transgenic mice overexpressing IRS-1 or IRS-2 in the mammary gland showed progressive mammary hyperplasia, tumorigenesis, and metastasis. Tumors showed extensive squamous differentiation, a phenotype commonly seen with activation of the canonical ␤-catenin signaling pathway. Consistent with this, IRSs were found to bind ␤-catenin in vitro and in vivo. IRS-induced tumorigenesis is unique, given that the IRSs are signaling adaptors with no intrinsic kinase activity, and this supports a growing literature indicating a role for IRSs in cancer. This study defines IRSs as oncogene proteins in vivo and provides new models to develop inhibitors against IRSs for anticancer therapy.Insulin receptor substrates (IRSs) are a family of intracellular proteins that integrate and coordinate hormone, cytokine, and growth factor signaling. To date, four IRS proteins (IRS-1 to IRS-4) have been identified (27). All IRSs contain multiple tyrosine phosphorylation sites that act as binding sites for SH2-containing proteins (27). The IRS proteins were first identified as substrates and presumed signaling intermediates of the insulin receptor. However, it is now clear that the IRS proteins can be activated and phosphorylated by a number of other signaling pathways, including those that are critical for mammary gland development, such as growth hormone and prolactin (2, 56).Much research has focused on the roles of IRSs in both metabolic and mitogenic signaling; however, the last several years have seen an emergence of literature implicating IRSs in human cancer. IRS-1 is constitutively active and phosphorylated in many tumors (6). IRS-1 levels are increased in patients with pancreatic cancer (1), and both IRS-1 and IRS-2 levels are increased in patients with hepatocellular cancer (3, 36). We previously reported that high IRS-1 levels are associated with poor outcomes for patients with breast cancer (25, 41), and this is supported by further studies showing that IRS-1 is expressed in patients with primary breast cancer and metastases, and its levels correlate with poor differentiation and lymph node involvement (22). One study, however, found that IRS-1 levels in advanced primary breast cancers were reduced compared to breasts from healthy patients (44).The mouse mammary gland has served as a useful area for the identification and characterization of oncogenes and tumor suppressor genes important in human breast cancer (15). For example, transgenic mice overexpressing the HER-2 oncogene develop mammary cancer with biological and phenotypic variances similar to those observed in human breast cancer patients (23).To date, there have been no re...

No abstract

The insulin-like growth factor (IGF) ligands stimulate cellular proliferation and survival by activating the type I insulin-like growth factor receptor (IGF-IR). As a result, the IGF signaling system is implicated in a number of cancers, including those of the breast, prostate, and lung. In addition to mitogenic and anti-apoptotic roles that may directly influence tumor development, IGF-IR also appears to be a critical determinant of response to numerous cancer therapies. This review describes the role of the IGF-IR pathway in mediating resistance to both general cytotoxic therapies, such as radiation and chemotherapy, and targeted therapies, such as tamoxifen and trastuzumab. It concludes with a description of approaches to target IGF-IR and argues that inhibition of IGF signaling, in conjunction with standard therapies, may enhance the response of cancer cells to multiple modalities.

Manganese (Mn), an essential element considered important for normal growth and reproduction, has been shown in adults to be detrimental to reproductive function when elevated. Because Mn can cross the blood-brain barrier and accumulate in the hypothalamus, and because it has been suggested that infants and children are potentially more sensitive to Mn than adults, we wanted to determine the effects of Mn exposure on puberty-related hormones and the onset of female puberty. We demonstrated that MnCl(2) when administered acutely into the third ventricle of the brain acts dose-dependently to stimulate luteinizing hormone (LH) release in prepubertal female rats. Incubation of hypothalami in vitro showed that this effect was due to a Mn-induced stimulation of luteinizing hormone releasing hormone (LHRH). Further demonstration that this is a hypothalamic site of action was shown by in vivo blockade of LHRH receptors and lack of a direct pituitary action of Mn to stimulate LH in vitro. To assess potential short-term effects, animals were supplemented with MnCl(2) (10 mg/kg) by gastric gavage from day 12 until day 29, or, in other animals, until vaginal opening (VO). Mn caused elevated serum levels of LH, follicle stimulating hormone, and estradiol, and it initiated a moderate but significant advancement in age at VO. Our results are the first to show that Mn can stimulate specific puberty-related hormones and suggest that it may facilitate the normal onset of puberty. They also suggest that Mn may contribute to precocious puberty if an individual is exposed to elevated levels of Mn too early in development.

No abstract

The precise role of circulating IGF-I in somatic growth under normal and GH-deficient conditions remains unclear. To define the contribution of circulating IGF-I to the endocrine regulation of somatic growth and the GH/IGF-I axis, we constructed a transgene with the transthyretin (TTR) enhancer/promoter and the mouse IGF-I cDNA and generated TTR-IGF-I transgenic mice. The transgene was exclusively expressed in the liver, which resulted in a 50-60% increase in serum IGF-I, a decrease in serum GH, and an improved tolerance to glucose challenge. The body weight and lean mass of TTR-IGF-I mice were heavier compared with wild-type (WT) mice. The increase in lean mass was a result of increase in both number and thickness of skeletal muscle fibers. The femur, tibia, and body lengths of TTR-IGF-I mice also were longer. In WT mice, the GH antagonist pegvisomant (Peg) suppressed the transcription of endogenous IGF-I and acid-labile subunit (ALS) genes with no effect on IGF-binding protein 3 (IGFBP-3) mRNA. Consequently, Peg-induced GH deficiency in WT mice severely reduced ALS, IGF-I, and IGFBP-3 in the circulation and caused a severe growth deficit. In TTR-IGF-I mice, Peg reduced the mRNA of the endogenous IGF-I gene with no effect on the TTR-IGF-I transgene expression, leading to a blunted decrease in serum IGF-I levels. Interestingly, IGFBP-3 mRNA was elevated and circulating IGFBP-3 was less reduced in Peg-treated TTR-IGF-I mice. Peg-treated TTR-IGF-I mice also exhibited heavier body weight and longer body length than Peg-treated WT mice. Therefore, liver-expressed IGF-I can stimulate IGFBP-3 mRNA expression and stabilize IGFBP-3 under GH deficiency, leading to a better maintenance of IGF-I levels in the circulation. Higher circulating levels of IGF-I can stimulate somatic growth and lean mass and improve glucose tolerance.

Questing is a host-seeking behavior in which ticks ascend plants, extend their front legs, and wait poised for a chance to attach to a passing host. Hard ticks are ectoparasites of terrestrial vertebrates and because some species vector disease, they are among the most medically important of arthropod pests. All ixodid ticks require blood to survive and reproduce with the number of blood-hosts needed to complete their life cycle varying among species. The vast majority are three-host ticks requiring a different host for each developmental stage: larva, nymph, and adult. A few, including some of the most economically important species, are one-host ticks, that quest only in the larval stage. Questing is a rate-limiting behavior critical to tick survival and disease transmission. For the off-host larval stage, survival is highly dependent on ecological and physiological factors. Yet, off-host larval ecophysiology is often overlooked for the more obvious adult and nymphal tick-host interactions. This review summarizes the literature on ixodid larval questing with emphasis on how specific biotic and abiotic factors affect off-host survival.

No abstract