Insulin-like growth factor binding protein 5 and apoptosis in mammary epithelial cells.
Insulin-like growth factors (IGFs) are important survival signals that can protect a range of cell types from apoptosis. Although IGF bioavailability is modulated by high affinity interactions with IGF-binding proteins (IGFBPs), there is currently no experimental evidence that IGFBPs regulate the survival function of IGFs in the mammary gland. We have examined IGFBP expression during mammary gland development and studied the effects of IGFBPs on IGF-mediated survival and signalling in mammary epithelial cells in culture. IGFBP-5 protein was greatly increased during days 1-3 of mammary gland involution, when levels of apoptosis are dramatically elevated to remodel the gland after lactation. Primary cultures of mammary epithelial cells (MECs) expressed IGFBP-5 from their basal surface suggesting that IGFBP-5 is suitably located to inhibit IGF signalling. Addition of exogenous IGFBP-5 and IGFBP-3 to MECs suppressed IGF-I-mediated survival, resulting in threefold greater apoptosis in cells incubated with IGF-I and IGFBP-5 compared with IGF-I alone. Examination of signalling pathways involved in apoptosis revealed that phosphorylation of PKB and the forkhead transcription factor, FKHRL1, was induced by IGFs, but that phosphorylation was blocked by IGFBP-5 and IGFBP-3. This study provides evidence that IGFBP-5 plays an important role in the regulation of apoptosis in the mammary gland.
Marshman
Emma
E
School of Biological Sciences, Stopford Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
Green
Kirsty A
KA
Flint
David J
DJ
White
Anne
A
Streuli
Charles H
CH
Westwood
Melissa
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism / Q000494:pharmacology; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism* / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007774:Lactation / Q000502:physiology; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D004268:DNA-Binding Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D018972:Insulin-Like Growth Factor Binding Protein 3; D018975:Insulin-Like Growth Factor Binding Protein 5; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt