NUCLEAR FACTOR OF KAPPA LIGHT CHAIN GENE ENHANCER IN B CELLS INHIBITOR, NFKBI|NUCLEAR FACTOR KAPPA-B INHIBITOR|INHIBITOR OF KAPPA LIGHT CHAIN GENE ENHANCER IN B CELLS, ALPHA|I-KAPPA-B-ALPHA, IKBA|ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH T-CELL IMMUNODEFICIE
NFKB1 (OMIM 164011) or NFKB2 (OMIM 164012) is bound to REL (OMIM 164910), RELA, or RELB (OMIM 604758) to form the NFKB complex. The p50 (NFKB1)/p65 (RELA) heterodimer is the most abundant form of NFKB. The NFKB complex is inhibited by I-kappa-B proteins (NFKBIA, OMIM 164008 or NFKBIB, OMIM 604495), which inactivate NFKB by trapping it in the cytoplasm. Phosphorylation of serine residues on the I-kappa-B proteins by kinases (IKBKA, OMIM 600664, or IKBKB, OMIM 603258) marks them for destruction via the ubiquitination pathway, thereby allowing activation of the NFKB complex. Activated NFKB complex translocates into the nucleus and binds DNA at kappa-B-binding motifs.
NCBI Summary:
NFKB1 (MIM 164011) or NFKB2 (MIM 164012) is bound to REL (MIM 164910), RELA (MIM 164014), or RELB (MIM 604758) to form the NFKB complex. The NFKB complex is inhibited by I-kappa-B proteins (NFKBIA or NFKBIB, MIM 604495), which inactivate NF-kappa-B by trapping it in the cytoplasm. Phosphorylation of serine residues on the I-kappa-B proteins by kinases (IKBKA, MIM 600664, or IKBKB, MIM 603258) marks them for destruction via the ubiquitination pathway, thereby allowing activation of the NF-kappa-B complex. Activated NFKB complex translocates into the nucleus and binds DNA at kappa-B-binding motifs such as 5-prime GGGRNNYYCC 3-prime or 5-prime HGGARNYYCC 3-prime (where H is A, C, or T; R is an A or G purine; and Y is a C or T pyrimidine).[supplied by OMIM]
General function
DNA binding, Transcription factor
Comment
Cellular localization
Cytoplasmic, Nuclear
Comment
Ovarian function
Follicle atresia, 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
Growth Factors/ cytokines
Comment
Wu Xiao C, et al reported that nuclear factor kappaB-mediated induction of Flice-like inhibitory protein prevents tumor necrosis factor alpha-induced apoptosis in rat granulosa cells.
The purpose of the studies was to examine the role and regulation of the antiapoptotic Flice-like inhibitory protein (FLIP) in rat granulosa cells by tumor necrosis factor alpha (TNFalpha) in vitro. Granulosa cells from immature rats primed with eCG were cultured in serum-free RPMI in the absence or presence of TNFalpha (20 ng/ml), cycloheximide (CHX, 10 microg/ml), SN50 (a specific inhibitor of nuclear factor kappaB [NFkappaB] translocation, 100 or 200 microg/ml), or a combination of these. (SM50, a mutated inactive peptide of SN50, was used as control.) Inhibitor kappaB (IkappaB; total and phosphorylated forms) and NFkappaB binding abilities were measured by Western blot and electrophoretic mobility shift assay, respectively. Apoptosis was assessed by in situ TUNEL assay, whereas FLIP mRNA levels were determined by semiquantitative reverse transcriptase-polymerase chain reaction. TNFalpha alone failed to induce granulosa cell death but significantly increased the apoptotic cell number in the presence of cycloheximide. TNFalpha significantly up-regulated the expression of the short form of FLIP (FLIP(S)) but not the long form (FLIP(L)). TNFalpha induced IkappaB phosphorylation and NFkappaB activation. SN50, but not SM50, attenuated TNFalpha-induced FLIP(S) expression and enhanced TNFalpha-induced apoptosis. Down-regulation of TNFalpha-induced FLIP(S) by FLIP(S) antisense expression enhanced TNFalpha-induced apoptosis. A full length of rat FLIP(S), with high homology to mouse FLIP(S) (85%), had been cloned and sequenced. These findings suggest that, in addition to its proapoptotic function, TNFalpha can induce an intracellular survival factor for the maintenance of follicular development. TNFalpha-induced, NFkappaB-mediated FLIP(S) expression is a determinant of granulosa cell fate.