Interaction of Brn3a and HIPK2 mediates transcriptional repression of sensory neuron survival
Open Access
- 18 October 2004
- journal article
- Published by Rockefeller University Press in The Journal of cell biology
- Vol. 167 (2) , 257-267
- https://doi.org/10.1083/jcb.200406131
Abstract
The Pit1-Oct1-Unc86 domain (POU domain) transcription factor Brn3a controls sensory neuron survival by regulating the expression of Trk receptors and members of the Bcl-2 family. Loss of Brn3a leads to a dramatic increase in apoptosis and severe loss of neurons in sensory ganglia. Although recent evidence suggests that Brn3a-mediated transcription can be modified by additional cofactors, the exact mechanisms are not known. Here, we report that homeodomain interacting protein kinase 2 (HIPK2) is a pro-apoptotic transcriptional cofactor that suppresses Brn3a-mediated gene expression. HIPK2 interacts with Brn3a, promotes Brn3a binding to DNA, but suppresses Brn3a-dependent transcription of brn3a, trkA, and bcl-xL. Overexpression of HIPK2 induces apoptosis in cultured sensory neurons. Conversely, targeted deletion of HIPK2 leads to increased expression of Brn3a, TrkA, and Bcl-xL, reduced apoptosis and increases in neuron numbers in the trigeminal ganglion. Together, these data indicate that HIPK2, through regulation of Brn3a-dependent gene expression, is a critical component in the transcriptional machinery that controls sensory neuron survival.Keywords
This publication has 50 references indexed in Scilit:
- Requirement of the Co-repressor Homeodomain-interacting Protein Kinase 2 for Ski-mediated Inhibition of Bone Morphogenetic Protein-induced Transcriptional ActivationJournal of Biological Chemistry, 2003
- Brn3a regulation of TrkA/NGF receptor expression in developing sensory neuronsDevelopment, 2003
- Direct autoregulation and gene dosage compensation by POU-domain transcription factor Brn3aDevelopment, 2003
- The Brn-3a transcription factor inhibits the pro-apoptotic effect of p53 and enhances cell cycle arrest by differentially regulating the activity of the p53 target genes encoding Bax and p21CIP1/Waf1Oncogene, 2002
- A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax genesOncogene, 2002
- Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2Nature Cell Biology, 2001
- Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosisNature Cell Biology, 2001
- Targeted deletion of the mouse POU domain gene Brn-3a causes selective loss of neurons in the brainstem and trigeminal ganglion, uncoordinated limb movement, and impaired suckling.Proceedings of the National Academy of Sciences, 1996
- Brn-3.0 expression identifies early post-mitotic CNS neurons and sensory neural precursorsMechanisms of Development, 1995
- Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogeneCell, 1991