Placental transforming growth factor-β is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression
Placental transforming growth factor-β is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression
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DOI：
10.1074/jbc.m909580199
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发表时间：
2000-06-30
影响因子：
4.8
通讯作者：
Klamut, HJ
中科院分区：
文献类型：
--
作者：
Li, PX;Wong, J;Klamut, HJ
p53肿瘤抑制基因和转化生长因子-β（TGF-β）超家族的成员在正常发育和分化以及癌发生中的信号传导细胞周期停滞和细胞凋亡（程序性细胞死亡）中起中心作用。在这里，我们描述了TGF-β超家族的远亲成员，指定胎盘TGF-β（PTGF-β），这是上调响应p53依赖性和非依赖性细胞凋亡信号事件所产生的DNA损伤在人乳腺癌细胞。PTGF-β通常在胎盘中表达，在肾、肺、胰腺和肌肉中表达较低，但在研究的任何肿瘤细胞系中均未检测到。PTGF-β启动子由p53激活，并含有两个p53结合位点基序。功能研究表明，这些p53结合位点之一是p53介导的PTGF-β启动子诱导所必需的，并在凝胶迁移率变动测定中特异性结合重组p53。重组腺病毒载体（AdPTGF-β）的PTGF-β过表达导致MDA-MB-468乳腺癌细胞活力降低80%，研究的其他人乳腺癌细胞系（包括MCF-7细胞）活力降低50-60%，MCF-7细胞对重组野生型p53的生长抑制具有抗性。像p53一样，PTGF-β过表达可以诱导乳腺肿瘤细胞的G（1）细胞周期停滞和凋亡。这些结果为p53和TGF-β超家族之间的直接功能联系提供了第一个证据，并暗示PTGF-β是p53功能以及放射和化疗癌症药物的细胞抑制作用的重要细胞间介质。
The p53 tumor suppressor gene and members of the transforming growth factor-beta (TGF-beta) superfamily play central roles in signaling cell cycle arrest and apoptosis (programmed cell death) in normal development and differentiation, as well as in carcinogenesis. Here we describe a distantly related member of the TGF-beta superfamily, designated placental TGF-beta (PTGF-beta), that is upregulated in response to both p53-dependent and -independent apoptotic signaling events arising from DNA damage in human breast cancer cells. PTGF-beta is normally expressed in placenta and at lower levels in kidney, lung, pancreas, and muscle but could not be detected in any tumor cell line studied. The PTGF-beta promoter is activated by p53 and contains two p53 binding site motifs, Functional studies demonstrated that one of these p53 binding sites is essential for p53-mediated PTGF-beta promoter induction and specifically binds recombinant p53 in gel mobility shift assays. PTGF-beta overexpression from a recombinant adenoviral vector (AdPTGF-beta) Led to an 80% reduction in MDA-MB-468 breast cancer cell viability and a 50-60% reduction in other human breast cancer cell lines studied, including MCF-7 cells, which are resistant to growth inhibition by recombinant wild-type p53. Like p53, PTGF-beta overexpression was seen to induce both G(1) cell cycle arrest and apoptosis in breast tumor cells. These results provide the first evidence for a direct functional link between p53 and the TGF-beta superfamily and implicate PTGF-beta as an important intercellular mediator of p53 function and the cytostatic effects of radiation and chemotherapeutic cancer agents.