THE ACTIVITY OF A 70 KILODALTON I-KAPPA-B MOLECULE IDENTICAL TO THE CARBOXYL-TERMINUS OF THE P105 NF-KAPPA-B PRECURSOR IS MODULATED BY PROTEIN-KINASE A
- Author(s)
- Gerondakis, S; MORRICE, N; RICHARDSON, IB; WETTENHALL, R; FECONDO, J; Grumont, RJ;
- Details
- Publication Year 1993-08,Volume 4,Issue #8,Page 617-627
- Journal Title
- CELL GROWTH & DIFFERENTIATION
- Publication Type
- Journal Article
- Abstract
- The p50 subunit of NF-kappaB is derived from the amino terminus of a 105 kilodalton precursor. The p105 carboxyl terminus, which contains ankyrin-like repeats, a feature of IkappaB molecules, regulates the cytoplasmic retention of p105 and inhibits DNA binding by the precursor. Here, we describe an IkappaB protein identical to the carboxyl-terminal region of p105. Probes spanning the COOH terminus but not the rel homology domain of p105 hybridize to a distinct 2.6-kilobase mRNA expressed in a wide range of murine tissues. The nucleotide sequence of complementary DNA clones for this transcript, in vitro translation, and immune precipitation of metabolically labeled cell lysates establish that it encodes a 70 kilodalton protein that corresponds to the COOH-terminal 607 amino acids of p105. p70 suppresses p65 and p75c-rel mediated trans-activation of reporter genes under the control of NF-kappaB elements and in vitro can prevent DNA binding of p50 and p75c-rel homodimers to NF-kappaB sites. The ability of p70 to stably associate with p49 and p65 in vitro, but not inhibit DNA binding by these proteins, suggests that the specific inhibitory properties of this IkappaB may reflect its relative affinity for different rel targets. p70 phosphorylated by protein kinase A fails to inhibit DNA binding by p50 or the c-rel protein, and sequencing of radiolabeled p70 tryptic phosphopeptides establishes that protein kinase A phosphorylates serine residue 576 of p70. This finding suggests that the inhibitory activity of p70 can be regulated by signaling via the adenylate cyclase pathway.
- Publisher
- AMER ASSOC CANCER RESEARCH
- Keywords
- DNA-BINDING SUBUNIT; REL-ASSOCIATED PP40; CELL-CYCLE CONTROL; TRANSCRIPTION ACTIVATOR; NUCLEOTIDE-SEQUENCE; ERYTHROCYTE ANKYRIN; PROTOONCOGENE BCL-3; 65-KD SUBUNIT; P50 PRECURSOR; GENE
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Creation Date: 1993-08-01 12:00:00