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J. Biol. Chem., Vol. 279, Issue 35, 37069-37078, August 27, 2004

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NPDC-1, a Novel Regulator of Neuronal Proliferation, Is Degraded by the Ubiquitin/Proteasome System through a PEST Degradation Motif^*

Michael L. Spencer, Maria Theodosiou, and Daniel J. Noonan

From the Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536

Neural proliferation and differentiation control protein-1 (NPDC-1) is a protein expressed primarily in brain and lung and whose expression can be correlated with the regulation of cellular proliferation and differentiation. Embryonic differentiation in brain and lung has classically been linked to retinoid signaling, and we have recently characterized NPDC-1 as a regulator of retinoic acid-mediated events. Regulators of differentiation and development are themselves highly regulated and usually through multiple mechanisms. One such mechanism, protein degradation via the ubiquitin/proteasome degradation pathway, has been linked to the expression of a number of proteins involved in control of proliferation or differentiation, including cyclin D1 and E2F-1. The data presented here demonstrate that NPDC-1 is likewise degraded by the ubiquitin/proteasome system. MG-132, a proteasome inhibitor, stabilized the expression of NPDC-1 and allowed detection of ubiquitinated NPDC-1 in vivo. A PEST motif (rich in proline, glutamine, serine, and threonine) located in the carboxyl terminus of NPDC-1 was shown to target the protein for degradation. Deletion of the PEST motif increased NPDC-1 protein stability and NPDC-1 inhibitory effect on retinoic acid-mediated transcription. NPDC-1 was phosphorylated by several kinases, including extracellular signal-regulated kinase. Phosphorylation of NPDC-1 increased the in vitro rate of NPDC-1 ubiquitination. The MEK inhibitor, PD-98059, an inhibitor of extracellular signal-regulated activation, also inhibited the formation of ubiquitinated NPDC-1 in vivo. Together these results suggest that retinoic acid signaling can be modulated by the presence of NPDC-1 and that the protein level and activity of NPDC-1 can be regulated by phosphorylation-mediated proteasomal degradation.

Received for publication, March 30, 2004 , and in revised form, June 22, 2004.

^* These studies were supported by the Kentucky Lung Cancer Research Program and by National Institutes of Health Grant HL67321 (to D. J. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Molecular and Cellular Biochemistry, University of Kentucky Medical Center, 800 Rose St., Lexington, KY 40536. Tel.: 859-247-7498; Fax: 859-323-1036; E-mail: dnoonan{at}uky.edu.

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