Mechanism of expression and role in transcriptional control of the proto-oncogene NFKB-2/LYT-10.
The NFKB-2 gene (previously LYT-10, NF-kappa Bp100 or NF-kappa Bp97) codes for a NF-kappa B/rel related protein which is highly homologous to NFKB-1 (previously NF-kappa Bp105) within its rel, poly-glycine and ankyrin domains. The NFKB-2 gene is a candidate proto-oncogene since it is involved in lymphoma-associated chromosomal aberrations. In order to gain insight into the physiological function and role in tumorigenesis of NFKB-2, we have analysed its mechanism of expression and role in transcriptional regulation. We report that, contrary to previous studies, a single 3.2 kb mRNA species and its 100 kD (p100) primary translation product is detectable in all cell types tested. A second NFKB-2 protein, p52, corresponding to the amino-terminal half (rel domain) of NFKB-2 p100, is detectable in the same cell types and derives from the post-translational processing of p100. While p100 is constitutively localized in the cytoplasm, NF-kappa B induction by TPA treatment of Hela cells is associated with cytoplasmic/nuclear translocation of NFKB-2 p52 and its appearance within DNA-binding NF-kappa B complexes. NFKB-2 p52 differs from NFKB-1p50 in its differential affinity for kappa B sequences: by itself it binds H2/HLA-kappa B sites more efficiently than HIV/IgK-kappa B sites, while it can bind both sites efficiently when complexed with Rel-A(p65). Transient co-transfection of expression and reporter plasmids in cells devoid of endogenous NF-kappa B activity showed that p52 has no intrinsic transcriptional activation capabilities: it can stimulate Rel-A(p65)-driven transcription by formation of p65/p52 heterodimers, whereas, overexpressed, it down-regulates p65-dependent transcription by formation of inactive p52/p52 homodimers. These results indicate that the NFKB-2 gene codes for an inducible NF-kappa B transcription factor with the capability of differentially regulating NF-kappa B transcription depending on its abundance in the nucleus.
Chang
C C
CC
Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
Zhang
J
J
Lombardi
L
L
Neri
A
A
Dalla-Favera
R
R
D000595:Amino Acid Sequence; D001483:Base Sequence; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics* / Q000502:physiology; D052003:NF-kappa B p52 Subunit; D011485:Protein Binding; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic
C000715470:MAS1 protein, human; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D004247:DNA; D013755:Tetradecanoylphorbol Acetate