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Mol Cell Biol, March 1998, p. 1312-1321, Vol. 18, No. 3
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Bone-Specific Expression of the Alpha Chain of the Nascent Polypeptide-Associated Complex, a Coactivator Potentiating c-Jun-Mediated Transcription

Alain Moreau, Wagner V. Yotov, Francis H. Glorieux, and René St-Arnaud^*

Genetics Unit, Shriners Hospital, and Departments of Surgery and Human Genetics, McGill University, Montréal, Québec H3G 1A6, Canada

Received 10 June 1997/Returned for modification 15 August 1997/Accepted 24 November 1997

The alpha chain of the nascent polypeptide-associated complex (-NAC) coactivator was shown to potentiate the activity of the homodimeric c-Jun activator, while transcription mediated by the c-Fos/c-Jun heterodimer was unaffected. The use of deletion mutants in pull-down assays revealed that -NAC interacted with amino acids 1 to 89 of the c-Jun protein and that the coactivator could interact with both the unphosphorylated and the serine 73-phosphorylated form of c-Jun. N-terminal-deleted c-Jun protein failed to interact with -NAC in mammalian two-hybrid assays, while mutant c-Jun proteins lacking the leucine zipper or the basic domain retained interaction with -NAC in vivo. Kinetics studies with purified c-Jun homodimer and recombinant -NAC proteins allowed determination of the mechanism of coactivation by -NAC: the coactivator stabilized the AP-1 complex formed by the c-Jun homodimer on its DNA recognition sequence through an eightfold reduction in the dissociation constant (k_d) of the complex. This effect of -NAC was specific, because -NAC could not stabilize the interactions of JunB or Sp1 with their cognate binding sites. Interestingly, the expression of -NAC was first detected at 14.5 to 15 days postconception, concomitantly with the onset of ossification during embryogenesis. The -NAC protein was specifically expressed in differentiated osteoblasts at the centers of ossification. Thus, the -NAC gene product exhibits the properties of a developmentally regulated, bone-specific transcriptional coactivator.

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^* Corresponding author. Mailing address: Genetics Unit, Shriners Hospital, 1529 Cedar Ave., Montréal, Québec H3G 1A6, Canada. Phone: (514) 842-5964. Fax: (514) 842-5581. E-mail: rst-arnaud{at}shriners.mcgill.ca.

Present address: Laboratoire de génétique moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.

Present address: Centre de cancérologie Charles Bruneau, Hôpital Ste-Justine, Montréal, Québec H3T 1C5, Canada.

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