Pleomorphic adenoma gene-like 2 regulates expression of the p53 family member, p73, and induces cell cycle block and apoptosis in human promonocytic U937 cells
Pleomorphic adenoma gene-like 2 regulates expression of the p53 family member, p73, and induces cell cycle block and apoptosis in human promonocytic U937 cells
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DOI：
10.1007/s10495-011-0672-3
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发表时间：
2012-03-01
期刊：
影响因子：
7.2
通讯作者：
Gauss, Katherine A.
中科院分区：
文献类型：
--
作者：
Hanks, Tracey S.;Gauss, Katherine A.
原癌基因多形性腺瘤基因样2(PLAGL2)与多种癌症有关，包括急性髓系白血病(AML)、恶性胶质瘤、结肠癌和肺腺癌。有更多证据表明，PLAGL2可以通过启动细胞周期停滞和凋亡而发挥肿瘤抑制作用。有趣的是，PLAGL2也与人类骨髓增生异常综合征有关，这是一种以无效造血为特征的疾病，可由于骨髓中细胞凋亡增加而导致致命的细胞减少症(低血细胞计数)，或在约三分之一的病例中，可进展为急性髓系白血病。为了更好地了解PLAGL2在人髓系细胞中的作用，我们用人原单核细胞U937细胞建立了稳定的PLAGL2诱导细胞系。PLAGL2的表达抑制了细胞的增殖，这与细胞在G1期的聚集、DNA梯状凋亡、caspase3、8和9活性的增加以及线粒体跨膜电位的丧失有关。P53同源基因p73和PLAGL2表达显著增加，与p73调控细胞周期调控和细胞凋亡的机制一致，已知的p73靶基因p21、DR5、TRAIL和Bax表达增加。在p73 siRNA存在的情况下，PLAGL2诱导的细胞周期阻滞被取消。综上所述，这些数据支持PLAGL2通过激活p73在细胞周期调节和细胞凋亡中的作用。
The proto-oncogene, pleomorphic adenoma gene-like 2 (PLAGL2), is implicated in a variety of cancers including acute myeloid leukemia (AML), malignant glioma, colon cancer, and lung adenocarcinoma. There is additional evidence that PLAGL2 can function as a tumor suppressor by initiating cell cycle arrest and apoptosis. Interestingly, PLAGL2 has also been implicated in human myelodysplastic syndrome, a disease that is characterized by ineffective hematopoiesis and can lead to fatal cytopenias (low blood counts) as a result of increased apoptosis in the marrow, or, in about one-third of cases, can progress to AML. To gain a better understanding of the actions of PLAGL2 in human myeloid cells, we generated a stable PLAGL2-inducible cell line, using human promonocytic U937 cells. PLAGL2 expression inhibited cell proliferation which correlated with an accumulation of cells in G1, apoptotic DNA-laddering, an increase in caspase 3, 8, and 9 activity, and a loss of mitochondrial transmembrane potential. There was significant increase in the p53 homologue, p73, with PLAGL2 expression, and consistent with mechanisms of p73-regulated cell cycle control and apoptosis, there was increased expression of known p73 target genes p21, DR5, TRAIL, and Bax. PLAGL2-induced cell cycle block was abolished in the presence of p73 siRNA. Together, these data support a role for PLAGL2 in cell cycle regulation and apoptosis via activation of p73.