SAA3 is a paralog of SAA1. -
NCBI Summary:
This gene encodes a member of the serum amyloid A family of apolipoproteins. The encoded protein is a major acute phase protein that is highly expressed in response to inflammation and tissue injury. This protein also plays an important role in HDL metabolism and cholesterol homeostasis. High levels of this protein are associated with chronic inflammatory diseases including atherosclerosis, rheumatoid arthritis, Alzheimer's disease and Crohn's disease. This protein may also be a potential biomarker for certain tumors. Alternate splicing results in multiple transcript variants that encode the same protein. A pseudogene of this gene is found on chromosome 11.[provided by RefSeq, Jun 2012]
General function
Extracellular binding protein
Comment
Cellular localization
Secreted
Comment
Ovarian function
Follicle development, Luteinization
Comment
CCAAT/Enhancer-Binding Proteins (C/EBP)-{alpha} and -{beta} Are Essential for Ovulation, Luteinization, and the Expression of Key Target Genes. Fan HY et al. LH activation of the epidermal growth factor receptor/RAS/ERK1/2 pathway is essential for ovulation and luteinization because granulosa cell (GC) depletion of Erk1/2 (Erk1/2(gc-/-) mice) renders mice infertile. As mediators of ERK1/2-dependent GC differentiation, the CCAAT/enhancer-binding proteins, (C/EBP)a and C/EBP? were also disrupted. Female Cebpb(gc-/-) mutant mice, but not Cebpa(gc-/-) mice, were subfertile whereas Cebpa/b(gc-/-) double-mutant females were sterile. Follicles failed to ovulate, ovaries were devoid of corpora lutea, luteal cell marker genes (Lhcgr, Prlr, Ptgfr, Cyp11a1, and Star) were absent, and serum progesterone levels were low. Microarray analyses identified numerous C/EBPa/?target genes in equine chorionic gonadotropin (eCG)-human (h)CG-treated mice. At 4 h post-hCG, a subset (19%) of genes altered in the Cebpa/b-depleted cells was also altered in Erk1/2-depleted cells; hence they are common effectors of ERK1/2. Additional genes down-regulated in the Cebpa/b-depleted cells at 8 and 24 h post-hCG include known (Akr1b7, Runx2, Star, Saa3) and novel (Abcb1b, Apln, Igfbp4, Prlr, Ptgfr Timp4) C/EBP targets and effectors of luteal and vascular cell development. Bhmt, a gene controlling methionine metabolism and thought to be expressed exclusively in liver and kidney, was high in wild-type luteal cells but totally absent in Cebpa/b mutant cells. Because numerous genes potentially associated with vascular development were suppressed in the mutant cells, C/EBPa/?appear to dictate the luteinization process by also controlling genes that regulate the formation of the extensive vascular network required to sustain luteal cells. Thus, C/EBPa/?mediate the terminal differentiation of GCs during the complex process of luteinization.
Serum amyloid A: Expression throughout human ovarian folliculogenesis and levels in follicular fluid of women undergoing controlled ovarian stimulation. Urieli-Shoval S 2013 et al.
Background:Serum amyloid A (SAA) is an acute phase protein expressed primarily in the liver in response to various injuries and inflammatory stimuli and is recognized as a modulator of inflammation. Ovarian reproductive functions including folliculogenesis and ovulation employ inflammatory processes, studying SAA in this context is thus of interest.Objectives:We investigated the expression and localization of SAA in ovarian developing follicles and its levels in follicular fluids.Methods and participants:Non-radioactive in situ hybridization and immunohistochemical staining were applied on ovarian paraffin tissue sections. ELISA and RT-PCR were applied on follicular aspirates and blood samples from women undergoing controlled ovarian stimulation for in vitro fertilization.Results:Expression of SAA mRNA and protein was found in follicular cells at all stages of follicular development, from primordial and primary follicles through antral follicles and corpora lutea. Expression was observed in granulosa, theca and luteal cells and in oocytes. Expression of SAA was also found in granulosa cells recovered from follicular aspirates. The SAA protein was detected in follicular fluids. Its levels were somewhat lower than in peripheral blood with strong correlation between the two compartments and with significant correlation with patient's body mass index. High follicular fluid SAA levels were associated with reduced pregnancy rate.Conclusions:SAA is locally produced in ovarian developing follicles and is a constituent of follicular fluids, suggesting its role within the follicular environment. Elevated follicular SAA levels are associated with decreased pregnancy rate and may signify lower reproductive performance.
/////////////////////////
Follicle stages
Antral, Preovulatory
Comment
Son DS, et al reported that tumor necrosis factor {alpha} (TNF) induces serum amyloid A3 in mouse granulosa cells.
Tumor necrosis factor alpha (TNF) has significant inhibitory effects on steroidogenesis and folliculogenesis and is associated with several inflammatory responses. Since ovulation is an inflammatory reaction, the effects of TNF on the family of acute-phase proteins in granulosa cells were investigated. Granulosa cells from immature mice at 28 days of age were cultured in the presence of 10 ng TNF/ml for 24 h. Serum amyloid A3 (SAA3), a main acute-phase protein, was induced by TNF in granulosa cells. The other isoforms of serum amyloid proteins SAA1, SAA2 and SAA4 were neither expressed in granulosa cells nor induced by TNF. TNF did not induce SAA3 mRNA in granulosa cells from TNFR1 knockout mice, although SAA3 mRNA was induced within 3 h after TNF treatment in wild-type cells. Two SAA3 promoters, -617/+73 and -198/+73, were responsive to TNF and to p65, a component of the TNF signaling molecule NF-kappaB. The -106/+73 promoter of SAA3 lacking a NF-kappaB like site was not responsive to TNF or p65. In granulosa cells from TNFR1 knockout mice, the SAA3 promoter (-198/+73) was responsive to transfection with the p65 component of NF-kappaB but neither TNF treatment nor over expression of the p50 component of NF-kappaB increased promoter activity. Similar results were observed in the murine ovarian granulosa tumor cell line (OV3121-1). Overexpression of the inhibitor of NF-kappaB (called IkappaB) blocked SAA3 promoter activity induced by TNF and by p65 in OV3121-1 cells. Closer analysis of deletion mutants of the SAA3 promoter revealed the necessity of a NF-kappaB like site for responsiveness to TNF in the OV3121-1 cells. TNF rapidly increased p65 in OV3121-1 nuclei when compared with controls not treated with TNF. TNF also increased phospho-IkB and SAA3 in whole cell homogenates as determined by Western blots. Thus, TNF likely increased SAA3 promoter activity and protein by activating NF-kappaB signaling via TNFR1 in mouse granulosa cells. SAA3 is a novel gene in granulosa cells with yet unknown functions in the ovary.