Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development

Conover, Cheryl A.; Bale, Laurie K.; Overgaard, Michael Toft; Johnstone, Edward W.; Laursen, Ulla L.; Füchtbauer, Ernst Martin; Oxvig, Claus; Deursen, Jan van

doi:10.1242/dev.00997

Cited by 255 publications

(223 citation statements)

References 41 publications

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“…The majority of IGF is synthesised within the liver and transported in the bloodstream bound to the IGFBPs. When bound to IGFBP4, IGF1 is biologically inactive but IGFBP4 can be cleaved by the IGFBP4-specific protease, PAPP-A, to release active IGF1 (Conover et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer

et al. 2009

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BACKGROUND: Insulin-like growth factor 1 (IGF1) promotes breast cancer and disease progression. Bioavailability of IGF1 is modulated by IGF-binding proteins (IGFBPs). IGFBP4 inhibits IGF1 activity but cleavage by pregnancy-associated plasma protein-A (PAPP-A) protease releases active IGF1. METHODS: Expression of IGF pathway components and PAPP-A was assessed by western blot or RT -PCR. IGFBP4 (dBP4) resistant to PAPP-A cleavage, but retaining IGF-binding capacity, was used to block IGF activity in vivo. 4T1.2 mouse mammary adenocarcinoma cells transfected with empty vector, vector expressing wild-type IGFBP4 or vector expressing dBP4 were implanted in the mammary fat pad of BALB/c mice and tumour growth was assessed. Tumour angiogenesis and endothelial cell apoptosis were assessed by immunohistochemistry. RESULTS: 4T1.2 cells expressed the IGF1R receptor and IGFBP4. PAPP-A was expressed within mammary tumours but not by 4T1.2 cells. Proliferation and vascular endothelial growth factor (VEGF) production by 4T1.2 cells was increased by IGF1(E3R) (recombinant IGF1 resistant to binding by IGFBPs) but not by wild-type IGF1. IGF1-stimulated microvascular endothelial cell proliferation was blocked by recombinant IGFBP4. 4T1.2 tumours expressing dBP4 grew significantly more slowly than controls or tumours expressing wild-type IGFBP4. Inhibition of tumour growth by dBP4 was accompanied by the increased endothelial cell apoptosis. CONCLUSION: Protease-resistant IGFBP4 blocks IGF activity, tumour growth and angiogenesis .

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Section: Discussionmentioning

confidence: 99%

Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer

et al. 2009

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“…Breeding stock for GHRKO mice was provided by Andrzej Bartke (Southern Illinois University, IL) and John Kopchick (Edison Biotechnology Institute of Ohio University, OH) and mice were produced as previously described (Dominick et al ., 2015). Breeding stock for PAPPA‐KO mice was provided by Cheryl Conover (Mayo Clinic, Rochester, MN) and mice were produced as previously described (Conover et al ., 2004). DW, GHRKO, and PAPPA‐KO mice were used at ages from 5 to 6 months.…”

Section: Methodsmentioning

confidence: 99%

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Dominick

Bowman

et al. 2016

Aging Cell

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SummaryStudies of the mTOR pathway have prompted speculation that diminished mTOR complex‐1 (mTORC1) function may be involved in controlling the aging process. Our previous studies have shown diminished mTORC1 activity in tissues of three long‐lived mutant mice: Snell dwarf mice, growth hormone receptor gene disrupted mice (GHRKO), and in this article, mice deficient in the pregnancy‐associated protein‐A (PAPPA‐KO). The ways in which lower mTOR signals slow aging and age‐related diseases are, however, not well characterized. Here, we show that Snell, GHKRO, and PAPPA‐KO mice express high levels of two proteins involved in DNA repair, O‐6‐methylguanine‐DNA methyltransferase (MGMT) and N‐myc downstream‐regulated gene 1 (NDRG1). Furthermore, we report that lowering mTOR enhances MGMT and NDRG1 protein expression via post‐transcriptional mechanisms. We show that the CCR4‐NOT complex, a post‐transcriptional regulator of gene expression, is downstream of the mTORC1 pathway and may be responsible for the upregulation of MGMT and NDRG1 in all three varieties of long‐lived mice. Our data thus suggest a novel link between DNA repair and mTOR signaling via post‐transcriptional regulation involving specific alteration in the CCR4‐NOT complex, whose modulation could control multiple aspects of the aging process.

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“…Disruption of the IGF-IR is also lethal in the perinatal period and results in severe growth retardation, whereas disruption of binding protein genes appears to produce mild non-lethal phenotypes [26,36]. The latter result suggests redundancy of IGFBP functions, which probably underestimates their role as negative regulators of growth, which has become more evident following further in vivo experiments [37]. As a result of the embryonic growth phenotypes, the function of these genes during adult life requires conditional modification to disrupt function, and tissue-specific or conditional expression to investigate gain of function.…”

Section: Insulin-like Growth Factor Ligand Receptor and Binding Promentioning

confidence: 99%

Insulin‐like growth factor ligands, receptors, and binding proteins in cancer

Foulstone

Prince

Zaccheo

et al. 2005

The Journal of Pathology

228

179

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This review aims to summarize experimental evidence supporting the role of the insulinlike growth factor (IGF) signalling system in the progression, maintenance, and treatment of cancer. These data implicate the IGF system as an important modifier of cancer cell proliferation, survival, growth, and treatment sensitivity. The role of the IGF system in cancer should be examined in the context of the extra-cellular and intra-cellular signalling networks, in particular: phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt/PKB), mammalian target of rapamycin (mTOR), and forkhead transcription factors (FOXO). This review highlights evidence derived from molecular structure and functional genetics with respect to how the extra-cellular components of the IGF system function normally, and their subsequent modifications in cancer. The therapeutic relevance of the research evidence described is also addressed, as the challenge is to apply this knowledge to human health.

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Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development

Cited by 255 publications

References 41 publications

Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer

Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Insulin‐like growth factor ligands, receptors, and binding proteins in cancer

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