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Evidence That the Insulin-Like Growth Factor Binding Protein-4 Protease in Human Ovarian Follicular Fluid Is Pregnancy Associated Plasma Protein-A
Abstract
Ovarian insulin-like growth factor binding protein-4 (IGFBP-4) proteolysis is involved in the regulation of follicular development, but until now the identity of the responsible enzyme was unknown. In this study, we identify the IGFBP4 protease in human follicular fluid as pregnancy associated plasma protein-A (PAPP-A) based on distinctive IGFBP-4 cleavage pattern, the same protease inhibitor profile, specific inhibition and immunodepletion of IGFBP-4 protease activity with PAPP-A polyclonal antibodies, and immunorecognition by PAPP-A monoclonal antibodies in ELISA. Furthermore, PAPP-A levels in estrogen-dominant and androgen-dominant follicular fluids reflect their IGFBP-4 proteolytic activity. PAPP-A was also secreted by human granulosa cells, the reputed source of IGFBP-4 protease activity in follicular fluid. We have the molecular and biochemical tools to begin to delineate the regulation and biological function of PAPP-A in normal and dysregulated follicular development and atresia.
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“A high concentration of this protein is found in the serum of pregnant women (Silahtaroglu et al. 1993; Conover et al. 1999; Lawrence et al. 1999).”
From Limb-Girdle Muscular Dystrophy Type 2H Associated with Mutation in TRIM32, a Putative E3-Ubiquitin–Ligase Gene (2002) · cites this paper as Conover et al. 1999
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Conover, C. A. (2012) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.02.008 · Cited by 624
Self-citationFortune, J. E., Rivera, G. M., & Yang, M. Y. (2004) · Animal Reproduction Science · doi:10.1016/j.anireprosci.2004.04.031 · Cited by 315
Laursen, L. S., Overgaard, M. T., Søe, R., et al. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02760-0 · Cited by 290
Self-citationOvergaard, M. T., Boldt, H. B., Laursen, L. S., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102191200 · Cited by 268
Self-citationFrosk, P., Weiler, T., Nylen, E., Sudha, T., Greenberg, C. R., Morgan, K., Fujiwara, T. M., & Wrogemann, K. (2002) · The American Journal of Human Genetics · doi:10.1086/339083 · Cited by 261
“A high concentration of this protein is found in the serum of pregnant women (Silahtaroglu et al. 1993; Conover et al. 1999; Lawrence et al. 1999).”
Background
Metadata
- Authors
- Conover, C. A., Oxvig, C., Overgaard, M. T., Christiansen, M., & Giudice, L. C.
- Affiliations
- Mayo Clinic (US)
- Aarhus University (DK)
- Statens Serum Institut (DK)
- Stanford Medicine (US)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1999-12
- Volume
- 84
- Issue
- 12
- Pages
- 4742-4745
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2051842303
- Cited by
- 120
- References
- 0
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 3 · 2017: 5 · 2016: 5 · 2015: 4 · 2014: 2 · 2013: 2 · 2012: 3
- FWCI
- 8.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD031579, HD 31579-05)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Reproductive Medicine › Reproductive Biology and Fertility
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Keywords
- IGFBP-4, PAPP-A, follicular fluid, granulosa cells, folliculogenesis, follicular atresia
- MeSH terms
- Edetic Acid, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Female, Fertilization in Vitro, Fibroblasts, Humans, Metalloendopeptidases, Phenanthrolines, Pregnancy-Associated Plasma Protein-A, Follicular Fluid, Culture Media, Conditioned, Insulin-Like Growth Factor Binding Protein 4
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