Rel-Associated pp40: an Inhibitor of the Rel Family of Transcription Factors

Abstract

The Rel-associated protein pp40 is functionally related to I kappa B, an inhibitor of the transcription factor NF-kappa B. Purified pp40 inhibits the DNA binding activity of the NF-kappa B protein complex (p50:p65 heterodimers), p50:c-Rel heteromers, and c-Rel homodimers. The sequence of the complementary DNA encoding pp40 revealed similarity to the gene encoding MAD-3, a protein with mammalian I kappa B-like activity. Protein sequencing of I kappa B purified from rabbit lung confirmed that MAD-3 encodes a protein similar to I kappa B. The sequence similarity between MAD-3 and pp40 includes a casein kinase II and consensus tyrosine phosphorylation site, as well as five repeats of a sequence found in the human erythrocyte protein ankyrin. These results suggest that rel-related transcription factors, which are capable of cytosolic to nuclear translocation, may be held in the cytosol by interaction with related cytoplasmic anchor molecules.

Shark, a Src homology 2, ankyrin repeat, tyrosine kinase, is expressed on the apical surfaces of ectodermal epithelia.

“…Unfortunately, by comparison to SH2 domains, much less is known about the structure and function of ANK repeats. However, in the few well-studied proteins-namely, Cactus (16), GABP,3 (18), NF-KB/I-KB (19), and ankyrin (20)-ANK repeats mediate regulated protein-protein interactions. Mutant forms of some ANK repeat proteins have been implicated in oncogenesis in mammals (21,22) and gross cell fate defects in Xenopus (23).…”

Multiple mutations contribute to the oncogenicity of the retroviral oncoprotein v-Rel

“…As such, our understanding of the complex interplay between the hundreds of genes and proteins whose expression is likely a ected in v-Reltransformed cells and of the contributions of their Lim et al, 1990Davis et al, 1991Capobianco et al, 1992Simek and Rice, 1988bMorrison et al, 1989Sif and Gilmore, 1994Xu et al, 1993Xu et al, 1993Koedood Zhao et al, 1999Gilmore and Temin, 1986Rice et al, 1986Tung et al, 1988bWalro et al, 1987 altered expression patterns to the transformed phenotype is meager.…”

“…This was ®rst apparent due to the fact that most of the v-Rel isolated from transformed chicken lymphoid cells was present in high molecular weight (approximately 300 ± 400 kDa) complexes and that immunoprecipitates of v-Rel contained a number of co-precipitating proteins (Davis et al, 1990;Kochel et al, 1991;Morrison et al, 1989;Simek and Rice, 1988a;Tung et al, 1988b). Shortly after the homology between v-Rel and NF-kB was discovered (Kieran et al, 1990), the major v-Rel co-precipitating proteins in vivo were identi®ed as cellular members of the Rel/NF-kB/IkB family: NFkB p105, NF-kB p100, c-Rel, and IkBa (Capobianco et al, 1990(Capobianco et al, , 1992Davis et al, 1991;. In addition, v-Rel is associated in transformed chicken lymphoid cells with several other unidenti®ed proteins that cross-react with certain Rel antibodies (Xu and Ge linas, 1995).…”

Two distinct mechanisms contribute to the constitutive activation of RelB in lymphoid cells.

“…In the meantime, several inhibitor proteins have been described (IKBa, IKB-0, IKB-,y and the protein encoded by the bcl-3 46© Oxford University Press gene) (Zabel and Baeuerle, 1990;Haskill et al, 1991;Inoue et al, 1992;Wulczyn et al, 1992) which differ in their specificity for different NF-KB/Rel proteins [for a review see Beg and Baldwin (1993)]. The best studied of the IKB proteins is IKB-a that inhibits RelA, RelB and cRel (Zabel and Baeuerle, 1990;Davis et dl., 1991;Haskill et al, 1991;Beg et al, 1992;Tewari et al, 1992;Zabel et al, 1993). In addition to sequestering the KB binding proteins in the cytoplasm by masking the nuclear localization sequence of these proteins, interaction with IKB-a in addition abolishes the DNA binding ability of these complexes (Zabel and Baeuerle, 1990;Beg et al, 1992;Zabel et al, 1993).…”