Insulin-like growth factor-binding protein-4 inhibits growth of the thymus in transgenic mice

Abstract

Numerous in vitro studies have demonstrated that IGF-binding protein (IGFBP)-4 is a consistent inhibitor of IGF actions. In order to investigate the functions of IGFBP-4 in vivo, transgenic mice were generated by microinjection of a transgene, in which the murine Igfbp4 cDNA is driven by the H-2K b promoter, and followed by a splicing cassette and polyadenylation signal of the human -globin gene. Transgene mRNA was expressed ubiquitously, and elevated IGFBP-4 protein was detected in the spleen, thymus, kidney and lung of transgenic mice. The activities of serum IGFBPs were not changed in transgenic mice. Immunohistochemical studies revealed transgene expression predominantly in the thymic medulla and red pulp of the spleen. Body weight and the weights of the spleen, kidney and lung of transgenic mice were not different from controls. In contrast, the thymus of transgenic mice showed a significantly reduced weight and cortex volume. In transgenic thymus and spleen, cell proliferation was inhibited and apoptosis was stimulated. Transgenic mice showed normal T-and B-cell development and normal basal plasma immunoglobulin levels. In conclusion, overexpression of IGFBP-4 inhibits growth of the thymus. IGFBP-4 excess inhibits cell proliferation and stimulates apoptosis in lymphoid tissues, but does not affect lymphocyte development. These findings suggest that IGFBP-4 is a potential growth inhibitor of lymphoid tissues.

Heat Shock Protein 90-Sheltered Overexpression of Insulin-Like Growth Factor 1 Receptor Contributes to Malignancy of Thymic Epithelial Tumors

“…Nevertheless, support that IGF-signaling might represent a potential oncogenic mechanism in TEMs stems from transgenic mice overexpressing either IGF-II or the IGF-binding protein 4 (IGFBP4). Whereas thymic size is markedly increased in the former mouse models (30,31), it is decreased in the latter, being associated with apoptosis (32). Consequently, the IGF-signaling axis that plays a relevant role in thymic epithelial cells under physiological conditions (33) might be exploited by an up-regulation of IGF-1R in TEMs to manifest the malignant phenotype.…”

Dynamic transcriptional regulation of autocrine/paracrine igfbp1, 2, 3, 4, 5, and 6 in the skeletal muscle of the fine flounder during different nutritional statuses

“…Igfbps regulate the half-life of circulating Igfs as well as modulating their availability and biological activity, either inhibiting or potentiating Igf 's actions depending on the EXP conditions, cell type, tissue, species, and physiological context (Wood et al 2000, Zhou et al 2004, Ning et al 2006, 2008, Ren et al 2008, Dai et al 2010, Amaral & Johnston 2011. Therefore, in the present work, the results were analyzed according to the physiological context of using two contrasting nutritional conditions: a catabolic period of fasting that leads to muscle atrophy followed by an anabolic period of refeeding that leads to hypertrophy of muscle.…”

Insulin-like Growth Factor Binding Protein-4 Differentially Inhibits Growth Factor-induced Angiogenesis

“…Among the six well characterized members of the IGFBP family, IGFBP-4 has been associated predominately with inhibitory functions such as reducing cellular proliferation and DNA synthesis as well as inducing apoptosis in a cell type-and tissuespecific manner (21,22). Importantly, studies have shown reduced levels of IGFBP-4 in malignant colon cancer as compared with normal colon tissues and, in addition, increasing the expression of IGFBP-4 in prostate and colon cancer cells slowed the growth of these tumors in vivo (23,24).…”