The inhibitor of cyclin-dependent kinase 4a/alternative reading frame (INK4a/ARF) locus encoded proteins p16INK4a and p19ARF repress cyclin D1 transcription through distinct cis elements
The inhibitor of cyclin-dependent kinase 4a/alternative reading frame (INK4a/ARF) locus encoded proteins p16INK4a and p19ARF repress cyclin D1 transcription through distinct cis elements
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DOI：
10.1158/0008-5472.can-03-2519
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发表时间：
2004-06-15
期刊：
影响因子：
11.2
通讯作者：
Pestell, RG
中科院分区：
文献类型：
--
作者：
D'Amico, M;Wu, KM;Pestell, RG
Ink 4a/Arf基因座编码两种结构上不相关的肿瘤抑制蛋白，p16（INK 4）和p14（ARF）（鼠p19（ARF））。p16（INK 4a）-细胞周期蛋白D/CDK-pRb通路和/或p53-p14（ARF）通路的恒定失活发生在大多数人类肿瘤中。细胞周期蛋白D1在乳腺癌细胞中经常过表达，导致p16（INK 4a）/pRb通路失活的另一种机制。针对乳腺的细胞周期蛋白D1的过表达对于肿瘤发生是足够的，并且细胞周期蛋白D1（-/-）小鼠对Ras诱导的乳腺肿瘤具有抗性。最近的研究表明，细胞周期蛋白D1和p16（INK 4a）的表达在人类乳腺癌是相互的。在此，在Ink 4a/Arf基因座突变小鼠的组织中观察到细胞周期蛋白D1和p16（INK 4）的相互调节。p16（INK 4a）和p19（ARF）抑制MCF 7细胞的DNA合成。p16（INK 4a）抑制cyclin D1的表达和转录。p16（INK 4a）对细胞周期蛋白D1的抑制作用不依赖于p16（INK 4a）-cdk 4结合功能，并且需要cAMP反应元件/激活转录因子2结合位点。p19（ARF）通过一个新的远端顺式元件-1137抑制细胞周期蛋白D1，该元件在染色质免疫沉淀试验中结合p53。通过不同的DNA序列的细胞周期蛋白D1基因的转录抑制可能有助于肿瘤抑制功能的Ink 4a/Arf基因座。
The Ink4a/Arf locus encodes two structurally unrelated tumor suppressor proteins, p16(INK4), and p14(ARF) (murine p19(ARF)). Invariant inactivation of either the p16(INK4a)-cyclin D/CDK-pRb pathway and/or p53-p14(ARF) pathway occurs in most human tumors. Cyclin D1 is frequently overexpressed in breast cancer cells contributing an alternate mechanism inactivating the p16(INK4a)/pRb pathway. Targeted overexpression of cyclin D1 to the mammary gland is sufficient for tumorigenesis, and cyclin D1(-/-) mice are resistant to Ras-induced mammary tumors. Recent studies suggest cyclin D1 and p16(INK4a) expression are reciprocal in human breast cancers. Herein, reciprocal regulation of cyclin D1 and p16(INK4) was observed in tissues of mice mutant for the Ink4a/Arf locus. p16(INK4a) and p19(ARF) inhibited DNA synthesis in MCF7 cells. p16(INK4a) repressed cyclin D1 expression and transcription. Repression of cyclin D1 by p16(INK4a) occurred independently of the p16(INK4a)-cdk4-binding function and required a cAMP-response element/activating transcription factor-2-binding site. p19(ARF) repressed cyclin D1 through a novel distal cis-element at -1137, which bound p53 in chromatin-immunoprecipitation assays. Transcriptional repression of the cyclin D1 gene through distinct DNA sequences may contribute to the tumor suppressor function of the Ink4a/Arf locus.