Kampa Kerstin M, Acoba Jared D, Chen Dexi, Gay Joel, Lee Hunjoo, Beemer Kelly, Padiernos Emerson, Boonmark Nataya, Zhu Zhiyi, Fan Alice C, Bailey Alexis S, Fleming William H, Corless Christopher, Felsher Dean W, Naumovski Louie, Lopez Charles D
Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR 97239, USA.
Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4390-5. doi: 10.1073/pnas.0809080106. Epub 2009 Feb 26.
The expression of ASPP2 (53BP2L), a proapoptotic member of a family of p53-binding proteins, is frequently suppressed in many human cancers. Accumulating evidence suggests that ASPP2 inhibits tumor growth; however, the mechanisms by which ASPP2 suppresses tumor formation remain to be clarified. To study this, we targeted the ASPP2 allele in a mouse by replacing exons 10-17 with a neoR gene. ASPP2(-/-) mice were not viable because of an early embryonic lethal event. Although ASPP2(+/-) mice appeared developmentally normal, they displayed an increased incidence of a variety of spontaneous tumors as they aged. Moreover, gamma-irradiated 6-week-old ASPP2(+/-) mice developed an increased incidence of high-grade T cell lymphomas of thymic origin compared with ASPP2(+/+) mice. Primary thymocytes derived from ASPP2(+/-) mice exhibited an attenuated apoptotic response to gamma-irradiation compared with ASPP2(+/+) thymocytes. Additionally, ASPP2(+/-) primary mouse embryonic fibroblasts demonstrated a defective G(0)/G(1) cell cycle checkpoint after gamma-irradiation. Our results demonstrate that ASPP2 is a haploinsufficient tumor suppressor and, importantly, open new avenues for investigation into the mechanisms by which disruption of ASPP2 pathways could play a role in tumorigenesis and response to therapy.
ASPP2（53BP2L）是一种p53结合蛋白家族的促凋亡成员，其表达在许多人类癌症中经常受到抑制。越来越多的证据表明ASPP2抑制肿瘤生长；然而，ASPP2抑制肿瘤形成的机制仍有待阐明。为了研究这一点，我们通过用neoR基因替换外显子10 - 17来靶向小鼠中的ASPP2等位基因。由于早期胚胎致死事件，ASPP2（- / -）小鼠无法存活。虽然ASPP2（+ / -）小鼠在发育上似乎正常，但随着年龄的增长，它们出现各种自发肿瘤的发生率增加。此外，与ASPP2（+ / +）小鼠相比，6周龄经γ射线照射的ASPP2（+ / -）小鼠发生胸腺起源的高级别T细胞淋巴瘤的发生率增加。与ASPP2（+ / +）胸腺细胞相比，源自ASPP2（+ / -）小鼠的原代胸腺细胞对γ射线照射表现出减弱的凋亡反应。此外，ASPP2（+ / -）原代小鼠胚胎成纤维细胞在γ射线照射后表现出缺陷的G（0）/ G（1）细胞周期检查点。我们的结果表明ASPP2是一种单倍剂量不足的肿瘤抑制因子，重要的是，为研究ASPP2途径的破坏在肿瘤发生和对治疗的反应中可能发挥作用的机制开辟了新途径。
