CSF1 is a novel p53 target gene whose protein product functions in a feed-forward manner to suppress apoptosis and enhance p53-mediated growth arrest.
CSF1 is a novel p53 target gene whose protein product functions in a feed-forward manner to suppress apoptosis and enhance p53-mediated growth arrest.
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DOI：
10.1371/journal.pone.0074297
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Murphy ME
中科院分区：
文献类型：
--
作者：
Azzam G;Wang X;Bell D;Murphy ME
P53抑癌基因在第72位密码子上有一个常见的多态，改变了它的功能。我们以前报道过P53(P72)的Proline 72多态变异体(P72)相对于精氨酸72(R72)表现出更强的反式激活基因子集的能力；其中一个基因是巨噬细胞集落刺激因子(CSF1)。目前，P72对CSF1等基因转录活性增强的机制(S)尚未完全阐明。此外，像CSF1这样的基因由P72变异体转录增加到下游的P53途径的后果尚不清楚。在本报告中，我们讨论了这些问题。我们发现CSF1基因包含一个保守的P53结合位点，有趣的是，P72变异体显示出与这个位点结合的能力增强。此外，我们发现，P72细胞中CSF1/CSF1R信号的增加反馈到P53途径，以提高P53的磷酸化水平和靶基因的反式激活，特别是细胞周期蛋白依赖的激酶抑制因子p21(CDKN1A)。这导致P53介导的生长停滞增加，伴随而来的是细胞凋亡的减少。值得注意的是，CSF1/CSF1R信号轴在几种上皮性癌症中过表达，临床证据表明，这一途径在某些癌症的放射抵抗中发挥了作用。我们表明，表达CSF1和CSF1R的细胞确实具有辐射抗性，而且这种作用需要p53。这些结合的数据首次表明CSF1/CSF1R通路在P53介导的生长抑制和细胞凋亡之间的决定中。他们还首次强调了一种细胞因子对上皮细胞中P53决定的细胞命运的影响。最后，这些数据可能解释了P72变异和CSF1/CSF1R通路与某些上皮性肿瘤类型衰老和放射抗性增加的关联。
The p53 tumor suppressor gene has a common polymorphism at codon 72 that alters its function. We previously reported that the proline 72 polymorphic variant of p53 (P72) demonstrates increased ability to transactivate a subset of genes, relative to arginine 72 (R72); one of these genes is macrophage colony stimulating factor (CSF1). At present, the mechanism(s) underlying the increased transcriptional activity of P72 toward genes like CSF1 have not been completely elucidated. Additionally, the consequences of increased transcription of genes like CSF1 by the P72 variant to the downstream p53 pathway are unknown. In this report, we address these issues. We show that the CSF1 gene contains a conserved binding site for p53, and interestingly that the P72 variant shows increased ability to bind to this site. Moreover, we show that increased CSF1/CSF1R signaling in P72 cells feeds back on the p53 pathway to enhance p53 phosphorylation, levels, and transactivation of target genes, particularly the cyclin-dependent kinase inhibitor p21 (CDKN1A). This leads to an increase in p53-mediated growth arrest, along with a concomitant decrease in apoptosis. Notably, the CSF1/CSF1R signaling axis is overexpressed in several epithelial cancers, and there is clinical evidence that this pathway plays a role in radio-resistance of some cancers. We show that cells expressing CSF1 and CSF1R are indeed radio-resistant, and further, that this effect requires p53. These combined data are the first to implicate the CSF1/CSF1R pathway in the decision between p53-mediated growth arrest and apoptosis. They are also the first to highlight a cytokine as influential in cell fate determined by p53 in epithelial cells. Finally, these data may explain the association of the P72 variant and the CSF1/CSF1R pathway with increased senescence and radio-resistance in some epithelial tumor types.
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