The Journal of Neuroscience, August 15, 2001, 21(16):5893-5901
A Dominant Negative Inhibitor of the Egr Family of Transcription
Regulatory Factors Suppresses Cerebellar Granule Cell Apoptosis by
Blocking c-Jun Activation
Yechiel
Levkovitz and
Jay M.
Baraban
Departments of Neuroscience, Psychiatry and Behavioral Sciences,
Johns Hopkins University School of Medicine, Baltimore, Maryland
21205
To investigate the role of the Egr family of transcription
regulatory factors in neuronal apoptosis, we examined the effect of a
dominant negative Egr inhibitor construct in a well characterized in vitro paradigm, cerebellar granule cell death induced
by withdrawal of depolarizing concentrations of extracellular
potassium. We found that this apoptotic stimulus increases the activity
of a reporter gene driven by the Egr response element and that a
dominant negative inhibitor of Egr-mediated transcription blocks
granule cell apoptosis. In contrast, apoptosis of immature granule
cells induced by cytosine arabinoside is not inhibited by the Egr
inhibitor construct. Because activation of c-Jun is an essential
step in granule cell death induced by potassium deprivation, but not
cytosine arabinoside, we asked whether the Egr inhibitor acts by
influencing c-Jun activation or its ability to induce apoptosis. We
found that the Egr inhibitor does not block the ability of a
constitutively active c-Jun construct to induce apoptosis in these
cells but does suppress activation of c-Jun-mediated transcription
induced by lowering extracellular potassium concentration. Furthermore, the Egr inhibitor blocks the ability of MEKK1 [mitogen-activated protein kinase (MAPK) kinase kinase 1], an upstream kinase
capable of stimulating the JNK (c-Jun N-terminal protein kinase)-c-Jun pathway, to induce apoptosis and activate c-Jun. Together, these studies indicate that the Egr family of transcription factors plays a
critical role in neuronal apoptosis and identify c-Jun activation as an
important downstream target of the Egr family in this process.
Key words:
Egr1; zif268; c-Jun; MEKK1; JNK; cytosine
arabinoside
Copyright © 2001 Society for Neuroscience 0270-6474/01/21165893-09$05.00/0
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