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C-terminal binding protein and poly(ADP)ribose polymerase 1 contribute to repression of the p21waf1/cip1 promoter

Oncogene volume 29, pages 6027–6039 (2010)Cite this article

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Abstract

Transcriptional repression by the C-terminal binding protein (CtBP) is proposed to require nicotinamide adenine dinucleotide dehydrogenase (NAD(H). Previous studies have implicated CtBP in transcriptional repression of the p21waf1/cip1 gene. Similarly, the NAD-dependent poly(adenosine diphosphate)ribose polymerase 1 (PARP1) may affect p21 expression via its NAD-dependent enzymatic activity; we therefore asked if PARP1 and CtBP were functionally linked in regulating p21 transcription. We found that restraint of basal p21 transcription requires both CtBP and PARP1. PARP inhibition attenuated activation of p21 transcription by both p53-independent and p53-dependent processes, in a CtBP-dependent manner. CtBP1+2 or PARP1+2 knockdown partially activated p21 gene expression, suggesting relief of a corepressor function dependent on both proteins. We localized CtBP-responsive repression elements to the proximal promoter region, and found ZBRK1 overexpression could also overcome DNA damage-dependent, but not p53-dependent activation through this region. By chromatin immunoprecipitation we find dismissal of CtBP from the proximal promoter following DNA-damage, and that PARP1 associates with a CtBP corepressor complex in nuclear extracts. We propose a model in which both CtBP and PARP functionally interact in a corepressor complex as components of a molecular switch necessary for p21 repression, and following DNA damage signals activation of p21 transcription by corepressor dismissal and co-activator recruitment.

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Acknowledgements

This work as supported by Grants (NIDDK R01DK060133) to JRL and DLM (NCI K08CA109158). We thank J Hildebrand (University of Pittsburgh) for the CtBP MEFs, R Klein (OHSU) for access to and assistance with real time PCR, R Kwok (University of Michigan) for the p53 expression construct and Madeleine Pham and Loren Brown for technical assistance.

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  1. Division of Endocrinology, Department of Medicine, Oregon Health and Sciences University, Portland, OR, USA

    D L Madison & J R Lundblad

  2. Department for Hospital and Specialty Medicine, Endocrine Section, Portland VA Medical Center, Portland, OR, USA

    D L Madison

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Correspondence to D L Madison.

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Madison, D., Lundblad, J. C-terminal binding protein and poly(ADP)ribose polymerase 1 contribute to repression of the p21waf1/cip1 promoter. Oncogene 29, 6027–6039 (2010). https://doi.org/10.1038/onc.2010.338

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