The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2
The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2
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DOI：
10.1093/emboj/17.17.5001
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发表时间：
1998-09-01
期刊：
影响因子：
11.4
通讯作者：
Peters, G
中科院分区：
文献类型：
--
作者：
Stott, FJ;Bates, S;Peters, G
由CDKN 2A基因座编码的两种不同的蛋白质通过在交替阅读框中翻译共同的第二外显子来指定。转录产物p16（INK 4a）是公认的肿瘤抑制因子，通过抑制细胞周期蛋白依赖性激酶CDK 4和CDK 6对视网膜母细胞瘤蛋白的磷酸化，诱导G（1）细胞周期停滞。相反，人CDKN 2A β转录产物p14（ARF）激活p53应答，表现为MDM 2和p21（CIP 1）水平升高以及G（1）和G（2）/M细胞周期停滞。因此，p14（ARF）诱导的细胞周期停滞是p53依赖性的，可以通过人乳头瘤病毒E6蛋白的共表达而被废除。p14（ARF）通过直接结合MDM 2起作用，导致p53和MDM 2的稳定。相反，p53负调控p14（ARF）的表达和p14（ARF）的表达和p53的功能在人类肿瘤细胞系之间存在负相关。然而，p14（ARF）表达不参与对DNA损伤的反应。这些结果将p14（ARF）置于p53上游的独立通路中，并暗示CDKN 2A编码两种参与肿瘤抑制的蛋白质。
The two distinct proteins encoded by the CDKN2A locus are specified by translating the common second exon in alternative reading frames. The product of the a transcript, p16(INK4a), is a recognized tumour suppressor that induces a G(1) cell cycle arrest by inhibiting the phosphorylation of the retinoblastoma protein by the cyclin-dependent kinases, CDK4 and CDK6. In contrast, the product of the human CDKN2A beta transcript, p14(ARF), activates a p53 response manifest in elevated levels of MDM2 and p21(CIP1) and cell cycle arrest in both G(1) and G(2)/M. As a consequence, p14(ARF) induced cell cycle arrest is p53 dependent and can be abrogated by the co-expression of human papilloma virus E6 protein. p14(ARF) acts by binding directly to MDM2, resulting in the stabilization of both p53 and MDM2. Conversely, p53 negatively regulates p14(ARF) expression and there is an inverse correlation between p14(ARF) expression and p53 function in human tumour cell lines. However, p14(ARF) expression is not involved in the response to DNA damage. These results place p14(ARF) in an independent pathway upstream of p53 and imply that CDKN2A encodes two proteins that are involved in tumour suppression.