Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis
Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis
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DOI：
10.1182/blood-2003-03-0971
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发表时间：
2003-12-01
期刊：
影响因子：
20.3
通讯作者：
Clapp, DW
中科院分区：
文献类型：
--
作者：
Freie, B;Li, XX;Clapp, DW
范可尼贫血（FA）是一种隐性基因组不稳定综合征，其特征是发育缺陷、进行性骨髓衰竭和癌症。然而，FA是遗传异质性的;由不同FA基因座编码的蛋白质在功能上相互作用，并与BRCA 1、BRCA 2和ATM基因产物相互作用。虽然FA患者极易发生髓性白血病和实体瘤，但这些患者中导致肿瘤发生进展的生化途径的改变仍不清楚。FA细胞对一系列遗传毒性和细胞应激高度敏感，这些应激激活介导细胞凋亡的信号通路。在这里，我们表明，电离辐射（IR）诱导适度升高水平的p53在FA型C（Fancc）突变小鼠的细胞和失活的Trp 53拯救肿瘤坏死因子α诱导的Fancc（-/-）小鼠骨髓细胞凋亡。此外，尽管Fancc（-/-）小鼠未能形成造血或实体恶性肿瘤，但Fancc和Trp 53突变的小鼠比单独Trp 53突变的小鼠更快地发展肿瘤。这种缩短的潜伏期与FA患者中发现的肿瘤类型的出现有关，但仅在Trp 53突变的小鼠中没有发现。总的来说，这些数据表明，p53和Fancc相互作用的功能，以调节Fancc缺陷细胞的凋亡和肿瘤发生。(C)2003年，美国血液学会。
Fanconi anemia (FA) is a recessive genomic instability syndrome characterized by developmental defects, progressive bone marrow failure, and cancer. FA is genetically heterogeneous, however; the proteins encoded by different FA loci interact functionally with each other and with the BRCA1, BRCA2 and ATM gene products. Although patients with FA are highly predisposed to the development of myeloid leukemia and solid tumors, the alterations in biochemical pathways responsible for the progression of tumor1- genesis in these patients remain unknown. FA cells are hypersensitive to a range of genotoxic and cellular stresses that activate signaling pathways mediating apoptosis. Here we show that ionizing radiation (IR) induces modestly elevated levels of p53 in cells from FA type C (Fancc) mutant mice and that inactivation of Trp53 rescues tumor necrosis factor alpha-induced apoptosis in myeloid cells from Fancc(-/-) mice. Further, whereas Fancc(-/-) mice failed to form hematopoietic or solid malignancies, mice mutant at both Fancc and Trp53 developed tumors more rapidly than mice mutant at Trp53 alone. This shortened latency was associated with the appearance of tumor types that are found in patients with FA but not in mice mutant at Trp53 only. Collectively, these data demonstrate that p53 and Fancc interact functionally to regulate apoptosis and tumorigenesis in Fancc-deficient cells. (C) 2003 by The American Society of Hematology.