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The Transcriptional Corepressor NAB2 Inhibits NGF-induced Differentiation of PC12 Cells

Qu, Zhican and Wolfraim, Lawrence A. and Svaren, John and Ehrengruber, Markus U. and Davidson, Norman and Milbrandt, Jeffrey (1998) The Transcriptional Corepressor NAB2 Inhibits NGF-induced Differentiation of PC12 Cells. Journal of Cell Biology, 142 (4). pp. 1075-1082. ISSN 0021-9525. http://resolver.caltech.edu/CaltechAUTHORS:QUZjcb98

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Abstract

The PC12 pheochromocytoma cell line responds to NGF by undergoing growth arrest and proceeding to differentiate toward a neuronal phenotype. Among the early genetic events triggered by NGF in PC12 cells are the rapid activation of the zinc finger transcription factor Egr1/NGFI-A, and a slightly delayed induction of NAB2, a corepressor that inhibits Egr1 transcriptional activity. We found that stably transfected PC12 cells expressing high levels of NAB2 do not differentiate, but rather continue to proliferate in response to NGF. Inhibition of PC12 differentiation by NAB2 overexpression was confirmed using two additional experimental approaches, transient transfection, and adenoviral infection. Early events in the NGF signaling cascade, such as activation of MAP kinase and induction of immediate-early genes, were unaltered in the NAB2-overexpressing PC12 cell lines. However, induction of delayed NGF response genes such as TGF-beta 1 and MMP-3 was inhibited. Furthermore, NAB2 overexpression led to downregulation of p21WAF1, a molecule previously shown to play a pivotal role in the ability of PC12 cells to undergo growth arrest and commit to differentiation in response to NGF. Cotransfection with p21WAF1 restored the ability of NAB2-overexpressing PC12 cells to differentiate in response to NGF.


Item Type:Article
Additional Information:© 1998 The Rockefeller University Press Received for publication 17 May 1998 and in revised form 7 July 1998. Z. Qu was supported by National Institutes of Health (NIH) National Research Award 15 F32 NS09935-02; J. Svaren by NIH National Research Award 1F32GM18058-01 from the National Institute of General Medical Sciences; and M.U. Ehrengruber by the Donald E. and Delia B. Baxter Foundation. This work was supported by NIH grant 5 P01 CA49712-08 (J. Milbrandt) and by National Institute of Mental Health (N. Davidson). We thank J. Johnson for providing the NAB2/Mader mAb, and M. Clements and B. Sevetson for helpful discussions. We also thank R. Heuckeroth, R. Nagarajan, W. Tourtellotte, and R. Baloh for comments on the manuscript.
Subject Keywords:Egr1; NAB2; p21WAF1; corepressor; differentiation
Record Number:CaltechAUTHORS:QUZjcb98
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:QUZjcb98
Alternative URL:http://www.jcb.org/cgi/content/abstract/142/4/1075
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:4666
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:02 Sep 2006
Last Modified:26 Dec 2012 09:00

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