NCBI Summary:
The protein encoded by this gene belongs to the NF-kappa-B inhibitor family, which inhibit NF-kappa-B by complexing with, and trapping it in the cytoplasm. Phosphorylation of serine residues on these proteins by kinases marks them for destruction via the ubiquitination pathway, thereby allowing activation of the NF-kappa-B, which translocates to the nucleus to function as a transcription factor. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jul 2011]
General function
Comment
Cellular localization
Cytoplasmic
Comment
Ovarian function
Initiation of primordial follicle growth, Luteolysis
Comment
Involvement of nuclear factor kappa B in the regulation of rat luteal function: potential roles as survival factor and inhibitor of 20alpha-hydroxysteroid dehydrogenase Telleria CM, et al .
Nuclear factor kappa B (NFkappaB) is an important intracellular conveyor of extracellular signals and modulates a number of gene responses. Due to the potential significance of NFkappaB in regulating ovarian gene expression, the authors examined in the rat: (i) whether NFkappaB is activated and developmentally regulated in the corpus luteum (CL) throughout pregnancy; (ii) the proteins forming the NFkappaB complex in luteal cells; and (iii) the role of this transcription factor in luteal function. Western analysis and immunohistochemistry revealed that p65 and p50 were highly expressed throughout pregnancy and were located in both the nucleus and cytoplasm of luteal cells. In addition, because NFkappaB is maintained in the cytoplasm bound to IkappaB, whose phosphorylation allows NFkappaB translocation to the nucleus, we studied the developmental expression of phosphorylated and nonphosphorylated forms of IkappaBalpha. Western analysis revealed that IkappaBalpha was present and phosphorylated throughout pregnancy in the CL whereas by protein/DNA array and electromobility shift assays we found that luteal nuclear extracts bind to an NFkappaB consensus sequence, and that the binding activity decreased along pregnancy. The specific binding was supershifted only by an anti-p65 antibody and not by antibodies against p50, p52, cRel, or RelB. Using day 4 postpartum ovaries, we found higher NFkappaB binding activity in the newly formed CL than in old CL of pregnancy. Furthermore, NFkappaB DNA binding activity was enhanced by prolactin in luteinized granulosa cells. In our first functional study, blockade of NFkappaB/p65 binding to DNA with the sesquiterpene lactone helenalin in luteinized granulosa cells correlated with induction of cell death in a dose-dependent manner. In a second functional study, overexpression of NFkappaB/p65 in luteal cells resulted in inhibition of 20alpha-hydroxysteroid dehydrogenase (20alphaHSD) promoter activity as well as endogenous 20alphaHSD mRNA expression. In summary, we have shown that: (i) NFkappaB is expressed within the CL, primary luteinized granulosa cells, and a rat luteal cell line; (ii) NFkappaB activation within the CL is developmentally regulated in pregnancy, depends on the age of the gland, and can be upregulated by prolactin; (iii) inhibition of NFkappaB/p65 binding to an NFkappaB DNA consensus sequence correlates with induction of cell death in ovarian luteinized granulosa cells; and (iv) overexpression of NFkappaB in luteal cells inhibits 20alphaHSD gene expression. The results further support a role for NFkappaB as a survival factor in the CL.
Expression regulated by
Steroids
Comment
Regulation of nuclear factor-kappaB (NF-kappaB) activity and apoptosis by estradiol in bovine granulosa cells.
Mol Cell Endocrinol. 2005 Oct 10; .
Ovarian localization
Luteal cells
Comment
Follicle stages
Corpus luteum
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: type: targeted overexpression fertility: fertile Comment: Control of Murine Primordial Follicle Growth Activation by IκB/NFκB Signaling. Wright CJ et al. (2020) The transcription factor NFκB has been associated with the timing of menopause in a large human genome-wide association study. Furthermore, preclinical studies demonstrate that loss of Tumor necrosis factor alpha (Tnfα) or its receptor Tnfr2 slows primordial follicle growth activation (PFGA). Although Tnfα:receptor signaling stimulates NFκB and may mechanistically link these findings, very little is known about NFκB signaling in PFGA. Because signaling downstream of Tnfα/Tnfr2 ligand/receptor interaction has not been interrogated as relates to PFGA, we evaluated the expression of key NFκB signaling proteins in primordial and growing follicles, as well as during ovarian aging. We show that key members of the NFκB pathway, including subunits, activating kinases, and inhibitory proteins, are expressed in the murine ovary. Furthermore, the subunits p65 and p50, and the cytosolic inhibitory proteins IκBα and IκBβ, are present in ovarian follicles, including at the primordial stage. Finally, we assessed PFGA in genetically modified mice (AKBI) previously demonstrated to be resistant to inflammatory stress-induced NFκB activation due to overexpression of the NFκB inhibitory protein IκBβ. Consistent with the hypothesis that NFκB plays a key role in PFGA, AKBI mice exhibit slower PGFA than wild-type (WT) controls, and their ovaries contain nearly twice the number of primordial follicles as WT both at early and late reproductive ages. These data provide mechanistic insight on the control of PFGA and suggest that targeting NFκB at the level of IκB proteins may be a tractable route to slowing the rate of PFGA in women faced with early ovarian demise.//////////////////