Moll U M, Ostermeyer A G, Haladay R, Winkfield B, Frazier M, Zambetti G
Department of Pathology, State Univeristy of New York at Stony Brook, New York 11792-8691, USA.
Mol Cell Biol. 1996 Mar;16(3):1126-37. doi: 10.1128/MCB.16.3.1126.
Wild-type p53 protein is abnormally sequestered in the cytoplasm of a subset of primary human tumors including neuroblastomas (NB) (U. M. Moll, M. LaQuaglia, J. Benard, and G. Riou, Proc. Natl. Acad. Sci. USA 92:4407-4411, 1995; U. M. Moll, G. Riou, and A. J. Levine, Proc. Natl. Acad. Sci.USA 89:7262-7266, 1992). This may represent a nonmutational mechanism for abrogating p53 tumor suppressor function. To test this hypothesis, we established the first available in vitro model that accurately reflects the wild-type p53 sequestration found in NB tumors. We characterized a series of human NB cell lines that overexpress wild-type p53 and show that p53 is preferentially localized to discrete cytoplasmic structures, with no detectable nuclear p53. These cell lines, when challenged with a variety of DNA strand-breaking agents, all exhibit impaired p53-mediated G1 arrest. Induction analysis of p53 and p53-responsive genes show that this impairment is due to suppression of nuclear p53 accumulation. Thus, this naturally occurring translocation defect compromises the suppressor function of p53 and likely plays a role in the tumorigenesis of these tumors previously thought to be unaffected by p53 alterations.
野生型p53蛋白在包括神经母细胞瘤（NB）在内的一部分原发性人类肿瘤细胞的细胞质中被异常隔离（U.M. Moll、M. LaQuaglia、J. Benard和G. Riou，《美国国家科学院院刊》92:4407 - 4411，1995；U.M. Moll、G. Riou和A.J. Levine，《美国国家科学院院刊》89:7262 - 7266，1992）。这可能代表了一种消除p53肿瘤抑制功能的非突变机制。为了验证这一假设，我们建立了第一个能够准确反映NB肿瘤中野生型p53隔离现象的体外模型。我们对一系列过表达野生型p53的人类NB细胞系进行了表征，结果显示p53优先定位于离散的细胞质结构中，而未检测到核内p53。当用多种DNA链断裂剂处理这些细胞系时，它们均表现出p53介导的G1期阻滞受损。对p53及其应答基因的诱导分析表明，这种损伤是由于核内p53积累受到抑制所致。因此，这种自然发生的易位缺陷损害了p53的抑制功能，并且可能在这些先前被认为不受p53改变影响的肿瘤的发生发展中起作用。
