Centrosomal Nlp is an oncogenic protein that is gene-amplified in human tumors and causes spontaneous tumorigenesis in transgenic mice
Shujuan Shao, … , Xiao Yang, Qimin Zhan
Shujuan Shao, … , Xiao Yang, Qimin Zhan
Published January 19, 2010
Citation Information: J Clin Invest. 2010;120(2):498-507. https://doi.org/10.1172/JCI39447.
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Research Article Oncology

Centrosomal Nlp is an oncogenic protein that is gene-amplified in human tumors and causes spontaneous tumorigenesis in transgenic mice

Abstract

Disruption of mitotic events contributes greatly to genomic instability and results in mutator phenotypes. Indeed, abnormalities of mitotic components are closely associated with malignant transformation and tumorigenesis. Here we show that ninein-like protein (Nlp), a recently identified BRCA1-associated centrosomal protein involved in microtubule nucleation and spindle formation, is an oncogenic protein. Nlp was found to be overexpressed in approximately 80% of human breast and lung carcinomas analyzed. In human lung cancers, this deregulated expression was associated with NLP gene amplification. Further analysis revealed that Nlp exhibited strong oncogenic properties; for example, it conferred to NIH3T3 rodent fibroblasts the capacity for anchorage-independent growth in vitro and tumor formation in nude mice. Consistent with these data, transgenic mice overexpressing Nlp displayed spontaneous tumorigenesis in the breast, ovary, and testicle within 60 weeks. In addition, Nlp overexpression induced more rapid onset of radiation-induced lymphoma. Furthermore, mouse embryonic fibroblasts (MEFs) derived from Nlp transgenic mice showed centrosome amplification, suggesting that Nlp overexpression mimics BRCA1 loss. These findings demonstrate that Nlp abnormalities may contribute to genomic instability and tumorigenesis and suggest that Nlp might serve as a potential biomarker for clinical diagnosis and therapeutic target.

Authors

Shujuan Shao, Rong Liu, Yang Wang, Yongmei Song, Lihui Zuo, Liyan Xue, Ning Lu, Ning Hou, Mingrong Wang, Xiao Yang, Qimin Zhan

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Figure 7

Analysis of MEFs derived from transgenic mice.

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Analysis of MEFs derived from transgenic mice. (A) MEFs isolated from bo...
(A) MEFs isolated from both normal and Nlp transgenic mice were plated in 30-mm tissue culture dishes, and cells were collected for counting each day. Three separate experiments were conducted. Data are presented as mean ± SEM; n = 6–9. (B) MEFs isolated from normal or Nlp transgenic mice were stained for centrosomes with γ-tubulin antibody and counterstained with DAPI. Arrows indicate the positions of centrosomes in MEFs derived from either normal (WT) or Nlp transgenic animals. Original magnification, ×400. (C) Quantitative results of centrosome analysis in MEFs were obtained from 3 separate experiments, and in each experiment, more than 400 cells were examined. Data represent percentages of cells with different centrosome copies and are presented as mean ± SEM. (D) Expression of Nlp-attenuated apoptosis induced by IR and UV radiation. MEFs from normal and Nlp transgenic mice were treated with IR at a dose of 15 Gy and UV radiation at a dose of 30 J/m2. Cells were collected 16 hours later for examination of apoptosis. Data are presented as mean ± SEM; n = 9–12.