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J. Biol. Chem., Vol. 282, Issue 24, 17712-17719, June 15, 2007

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Cell Cycle-dependent Expression of Centrosomal Ninein-like Protein in Human Cells Is Regulated by the Anaphase-promoting Complex^*

From the State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

The recently identified centrosome protein Nlp (ninein-like protein) is a key regulator in centrosome maturation, which contributes to chromosome segregation and cytokinesis. However, the mechanism(s) controlling Nlp expression remains largely unknown. Here we have shown that Nlp expression is cell cycle-dependent with a peak at G₂/M transition in human cells. Nlp is a short-lived protein and degraded by the proteasome via the anaphase-promoting cyclosome complex (APC/c) pathway. It interacts with the APC/c through the APC2 or Cdc27 subunits and is ubiquitinated. Following treatment with proteasome inhibitors, its protein level is elevated. Nlp binds in vivo to the degradation-targeting proteins Cdh1 and Cdc20, and overexpression of Cdh1 and Cdc20 enhances Nlp degradation. Using point mutations of the two putative degradation signals in Nlp, we have found that its degradation requires intact KEN-box and D-box. Interestingly, the Lys-Glu-Asn-D-box-mutated Nlp exhibits a much stronger capability of inducing anchorage-independent growth and multinuclearity compared with the wild type Nlp. Taken together, these findings indicate that Nlp expression is cell cycle-dependent and regulated by APC-mediated protein degradation.

Received for publication, February 15, 2007 , and in revised form, April 2, 2007.

^* This work was supported by funding from the 973 National Key Fundamental Research Program of China (2002 CB513101) and the National Natural Science Foundation of China (30225018). 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.

¹ To whom correspondence should be addressed: State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Cancer Institute, and Cancer Hospital, Beijing 100021, China. Tel.: 86-10-67762694; Fax: 86-10-67715058; E-mail: Zhanqimin{at}pumc.edu.cn.

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