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Constitutive NF-κB activation, enhanced granulopoiesis, and neonatal lethality in IκBα-deficient mice

Beg, Amer A. and Sha, William C. and Bronson, Roderick T. and Baltimore, David (1995) Constitutive NF-κB activation, enhanced granulopoiesis, and neonatal lethality in IκBα-deficient mice. Genes and Development, 9 (22). pp. 2736-2746. ISSN 0890-9369. doi:10.1101/gad.9.22.2736.

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Transcription factors belonging to the NF-κB family are controlled by inhibitory IκB proteins, mainly IκBα and IκBβ. Apparently normal at birth, IκBα^(-/-) mice exhibit severe runting, skin defects, and extensive granulopoiesis postnatally, typically dying by 8 days. Hematopoietic tissues from these mice display elevated levels of both nuclear NF-κB and mRNAs of some, but not all, genes thought to be regulated by NF-κB. NF-κB elevation results in these phenotypic abnormalities because mice lacking both IκBα and the p50 subunit of NF-κB show a dramatically delayed onset of abnormalities. In contrast to hematopoietic cells, IκBα^(-/-) embryonic fibroblasts show minimal constitutive NF-κB, as well as normal signal-dependent NF-κB activation that is concomitant with IκBβ degradation. Our results indicate that Iκbβ, but not IκBα, is required for the signal-dependent activation of NF-κB in fibroblasts. However, IκBα is required for the postinduction repression of NF-κB in fibroblasts. These results define distinct roles for the two forms of IκB and demonstrate the necessity for stringent control of NF-κB.

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Baltimore, David0000-0001-8723-8190
Alternate Title:Constitutive NF-kappa B activation, enhanced granulopoiesis, and neonatal lethality in I kappa B alpha-deficient mice
Additional Information:© 1995 Cold Spring Harbor Laboratory Press. Received August 23, 1995; revised version accepted September 22, 1995. We thank the transgenic facility at the Rockefeller University for help in generation of chimeric mice and Ann Gifford for help in genotyping. We also thank Richard Gallo (Children's Hospital, Boston), M. Scott, B. Horwitz, W. Pear, and other members of our laboratory for discussion. We apologize for not citing many primary sources because of constraints on the length of the text. A.A.B. was supported by a Concern II/Cancer Research Institute Fellowship. W.C.S. was supported by a fellowship from the National Institute of Health (NIH) (AI08724-02). This work was supported by NIH grant GM39458 to D.B. and by the Amgen Corporation. The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.
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Cancer Research InstituteUNSPECIFIED
Subject Keywords:NF-κB; IκB; transcription; granulopoiesis; gene targeting
Issue or Number:22
Record Number:CaltechAUTHORS:20200512-080705753
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103123
Deposited By: Tony Diaz
Deposited On:12 May 2020 19:06
Last Modified:16 Nov 2021 18:18

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