Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition
Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition
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DOI：
10.1074/jbc.m109.031641
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发表时间：
2009-12-25
影响因子：
4.8
通讯作者：
Dennery, Phyllis A.
中科院分区：
文献类型：
--
作者：
La, Ping;Fernando, Amal P.;Dennery, Phyllis A.
锌原卟啉IX（ZnPP）是一种内源性血红素类似物，可抑制血红素加氧酶（HO）活性，抑制肿瘤生长。它还可以易位到细胞核中并上调血红素加氧酶1（HMOX 1）基因的表达。在这里，我们证明，肿瘤细胞增殖抑制ZnPP，而锡原卟啉（SnPP），另一个同样有效的HO-1抑制剂，没有效果。对128个肿瘤发生相关基因的芯片分析显示，ZnPP抑制了参与细胞增殖和血管生成的基因。在这些基因中，细胞周期蛋白D1（CCND 1）被特异性抑制，其mRNA和蛋白质水平也是如此。此外，ZnPP通过Sp1和Egr 1重叠结合位点（S/E）抑制CCND 1启动子活性。我们证实，ZnPP调制的S/E网站，至少部分地通过与Sp1和Egr 1蛋白，而不是直接结合到DNA的目标。此外，ZnPP的管理显着抑制细胞周期蛋白D1的表达和发展的B细胞白血病/淋巴瘤1肿瘤小鼠优先靶向肿瘤细胞。这些观察结果显示了ZnPP对细胞周期蛋白D1表达和肿瘤发生的HO独立作用。
Zinc protoporphyrin IX (ZnPP), an endogenous heme analogue that inhibits heme oxygenase (HO) activity, represses tumor growth. It can also translocate into the nucleus and up-regulate heme oxygenase 1 (HMOX1) gene expression. Here, we demonstrate that tumor cell proliferation was inhibited by ZnPP, whereas tin protoporphyrin (SnPP), another equally potent HO-1 inhibitor, had no effect. Microarray analysis on 128 tumorigenesis related genes showed that ZnPP suppressed genes involved in cell proliferation and angiogenesis. Among these genes, CYCLIN D1 (CCND1) was specifically inhibited as were its mRNA and protein levels. Additionally, ZnPP inhibited CCND1 promoter activity through an Sp1 and Egr1 overlapping binding site (S/E). We confirmed that ZnPP modulated the S/E site, at least partially by associating with Sp1 and Egr1 proteins rather than direct binding to DNA targets. Furthermore, administration of ZnPP significantly inhibited cyclin D1 expression and progression of a B-cell leukemia/lymphoma 1 tumor in mice by preferentially targeting tumor cells. These observations show HO independent effects of ZnPP on cyclin D1 expression and tumorigenesis.