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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

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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 3

Anchorage-independent growth induced by Nlp expression.

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Anchorage-independent growth induced by Nlp expression.
(A) NIH3T3 cells...
(A) NIH3T3 cells were transfected with pEGFP-Nlp or empty vectors. Following G418 selection for 14 days, Nlp-expressing lines were established and analyzed by immunoblot assays. In the tumorigenic assays, pooled clone and 3 independent clones of NIH3T3 cells were used. (B) Cells (104) from Nlp-expressing cell lines (3T3-Pool, 3T3-53, 3T3-58, and 3T3-78) and the parental line (3T3) or 3T3-GFP were seeded in 100-mm dishes and grown in DMEM supplemented with 10% FBS. Cells were collected each day to count cell numbers. Data are presented as mean ± SEM; n = 9–12. (C) NIH3T3 or its isogenic cells (103) were seeded in 0.3% top agar and incubate at 37°C in a humidified incubator for 14 days. Nlp-expressing cells formed larger colonies in soft agar. Original magnification, ×20. (D) The quantitative results of colony formation were obtained. Data are presented as mean ± SEM; n = 9.

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