The rel-associated pp40 protein prevents DNA binding of Rel and NF-kappa B: relationship with I kappa B beta and regulation by phosphorylation.

Kerr, Lawrence D.; Inoue, Jun; Davis, Nathan; Link, Egenhard; Baeuerle, Patrick A.; Bose, Henry R.; Verma, Inder M.

doi:10.1101/gad.5.8.1464

Cited by 207 publications

(162 citation statements)

References 32 publications

(31 reference statements)

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“…The data presented here constitute the first demonstration in vivo of the involvement of a protein phosphatase in the activation of NF-xB through inactivation of IxB. In vitro, dephosphorylation of IxB-j3 inactivates it (Kerr et al, 1991;Link et al, 1992) suggesting that this class of IxB may be a substrate for calcineurin. However, the FK-506-sensitive appearance of a phosphorylated form of IxB ( Figure 6A and B) suggests the possibility that calcineurin activates a protein kinase, which inactivates IxB by phosphorylation.…”

Section: Discussionmentioning

confidence: 95%

Calcineurin acts in synergy with PMA to inactivate I kappa B/MAD3, an inhibitor of NF-kappa B.

et al. 1994

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The interleukin-2 (IL-2) promoter consists of several independent T cell receptor (TcR) responsive elements. The induction of promoters dependent on these elements is inhibitable by the immunosuppressants cyclosporin A (CsA) and tacrolimus . Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, is the FK-506-and CsA-sensitive enzyme required for TcR mediated activation of the LL-2 promoter. We report that a constitutively active form of calcineurin partially substitutes for the Ca2+ co-stimulus required to activate the IL-2 promoter elements IL-2A (which binds the factors OAP and Oct-i) and LL-2E (which binds NF-AT), and completely substitutes for the Ca2+ co-stimulus required to stimulate an NF-xB-dependent element. Calcineurin stimulates the NF-xB element by enhancing inactivation of IxB/MAD3, an inhibitor of NF-xB, thereby increasing the amount of nuclear NF-xB DNA binding activity. These data provide the first demonstration in vivo that activation of a protein phosphatase can inactivate IxB, and suggest one possible explanation for mechanism-based toxicities associated with FK-506 and CsA by demonstrating that these drugs can inhibit the calcineurin-dependent activation of a virtually ubiquitous transcription factor.

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Section: Discussionmentioning

confidence: 95%

Calcineurin acts in synergy with PMA to inactivate I kappa B/MAD3, an inhibitor of NF-kappa B.

et al. 1994

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“…ikba encodes the avian homologue of IkBa which was shown to be able to sequester the avian c-Rel protein in the cytoplasm and to inhibit its binding to DNA (Diehl et al, 1993;Kerr et al, 1991; Davis et al, Figure 4 Subcellular localization of c-Rel during apoptosis of medullary thymocytes. P1 thymus sections were processed for anti-c-Rel immunocytochemistry and observed at high magnification.…”

Section: The Ikba Gene Expression Decreases In Thymocytes During Apopmentioning

confidence: 99%

“…Since the activity of Rel/NF-kB proteins depends on interactions with IkB proteins that determine their nuclear or cytoplasmic localization, we have described the subcellular distribution of the c-Rel protein during the process of apoptosis together with the expression of ikba, the gene encoding the avian homologue of IkBa Kerr et al, 1991). Our results indicate that the c-Rel protein is expressed in thymocytes undergoing apoptosis through natural selection and moreover that c-Rel is induced and translocates into the nucleus of thymocytes during the time course of experimentally-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

The avian transcription factor c-Rel is induced and translocates into the nucleus of thymocytes undergoing apoptosis

et al. 1997

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This study investigates the involvement of the avian transcription factor c-Rel in thymocyte apoptosis occurring either in vivo or in organotypic culture. In vivo, only a few cortical thymocytes express the c-Rel protein. Their number, localization and morphology resemble that of apoptotic cells evidenced by TUNEL staining. In organotypic culture, the expression of c-Rel is induced in medullary thymocytes as apoptosis is triggered. This induction would be posttranscriptional since no increase in the c-rel gene expression is detected. Moreover, c-Rel translocates into the nucleus of medullary thymocytes during the time course of apoptosis. This translocation is preceded by a decrease in ikba expression, the gene which encodes the avian homologue of IkBa. Altogether these results suggest that the protooncogene c-rel could take an active part in apoptosis of cortical thymocytes occurring in vivo during T-cell selection as well as in experimentally-induced apoptosis of medullary thymocytes.

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“…IkBa is a potent inhibitor of c-Rel DNA-binding activity (Zabel and Baeuerle, 1990;Kerr et al, 1991). Since the sequences of IkBa implicated in the suppression of Rel DNA binding generally correspond to those important for the transcriptional inactivation of c-Rel (Luque and GeÂ linas, 1998), we postulated that the regulation of nuclear c-Rel activity by IkBa mutants 59 ± 318 and 76 ± 318 may result from the inhibition of c-Rel interaction with DNA.…”

mentioning

confidence: 99%

N-terminal determinants of IκBα necessary for the cytoplasmic regulation of c-Rel

Luque¹,

Zong²,

Chen³

et al. 2000

Oncogene

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IkBa is a dual regulator of Rel/NF-kB transcription factors. IkBa retains inactive NF-kB dimers in the cytoplasm, and inhibits their DNA-binding and transcriptional activities in the nucleus. Our previous studies identi®ed discrete functional domains in IkBa responsible for the cytoplasmic and nuclear regulation of c-Rel. Determinants necessary for regulating c-Rel in the nucleus mapped to the central ankyrin domain of IkBa and a few negatively-charged amino acids that follow in the C-terminal PEST region. In contrast, sequences involved in the cytoplasmic regulation of c-Rel reside in the N-terminal and central ankyrin domains of IkBa.Here, we present a re®ned mapping of the N-terminal determinants of IkBa necessary for the cytoplasmic regulation of c-Rel homodimers. We demonstrate that amino acids 48 ± 58 in p40/IkBa are essential to block the nuclear localization of c-Rel dimers. These data de®ne a region of IkBa that may be required for optimal masking of the c-Rel NLS, or for the nuclear export of c-Rel/IkBa complexes. These ®ndings highlight a novel function for the N-terminus of IkBa in the control of the subcellular localization of Rel/NF-kB dimers. Given the implication of deregulated NF-kB activity in hematopoietic and solid tumors, our ®ndings predict that certain alterations in this domain of IkBa may have severe biological repercussions.

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The rel-associated pp40 protein prevents DNA binding of Rel and NF-kappa B: relationship with I kappa B beta and regulation by phosphorylation.

Cited by 207 publications

References 32 publications

Calcineurin acts in synergy with PMA to inactivate I kappa B/MAD3, an inhibitor of NF-kappa B.

Calcineurin acts in synergy with PMA to inactivate I kappa B/MAD3, an inhibitor of NF-kappa B.

The avian transcription factor c-Rel is induced and translocates into the nucleus of thymocytes undergoing apoptosis

N-terminal determinants of IκBα necessary for the cytoplasmic regulation of c-Rel

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