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Breast Cancer Amplified Sequence 2, a Novel Negative Regulator of the p53 Tumor Suppressor

¹ Graduate Institute of Microbiology, College of Medicine, National Taiwan University; ² Department of Ophthalmology, Mackay Memorial Hospital; ³ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan and ⁴ Department of Microbiology & Immunology, National Chiayi University, Chiayi, Taiwan

Requests for reprints: Show-Li Chen, Graduate Institute of Microbiology, College of Medicine, National Taiwan University, 7F, No. 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan. Phone: 886-2-2312-3456, ext. 88289; Fax: 886-2-2391-5293; E-mail: showlic{at}ntu.edu.tw.

Breast cancer amplified sequence 2 (BCAS2) was reported previously as a transcriptional coactivator of estrogen receptor. Here, we report that BCAS2 directly interacts with p53 to reduce p53 transcriptional activity by mildly but consistently decreasing p53 protein in the absence of DNA damage. However, in the presence of DNA damage, BCAS2 prominently reduces p53 protein and provides protection against chemotherapeutic agent such as doxorubicin. Deprivation of BCAS2 induces apoptosis in p53 wild-type cells but causes G₂-M arrest in p53-null or p53 mutant cells. There are at least two apoptosis mechanisms induced by silencing BCAS2 in wild-type p53-containing cells. Firstly, it increases p53 retention in nucleus that triggers the expression of apoptosis-related genes. Secondly, it increases p53 transcriptional activity by raising p53 phosphorylation at Ser⁴⁶ and decreases p53 protein degradation by reducing p53 phosphorylation at Ser³¹⁵. We show for the first time that BCAS2, a small nuclear protein (26 kDa), is a novel negative regulator of p53 and hence a potential molecular target for cancer therapy. [Cancer Res 2009;69(23):OF1–9]

Key Words: apoptosis • BCAS2 • p21 • p53 • PUMA