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首页> 外文期刊>Oncogene >Human p16|[gamma]|, a novel transcriptional variant of p16INK4A, coexpresses with p16INK4A in cancer cells and inhibits cell-cycle progression
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Human p16|[gamma]|, a novel transcriptional variant of p16INK4A, coexpresses with p16INK4A in cancer cells and inhibits cell-cycle progression

机译：人p16 |γ|，p16INK4A的新型转录变异体，与p16INK4A在癌细胞中共表达并抑制细胞周期进程

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摘要

The INK4A locus encodes two tumor suppressor genes, p16INK4A and p14ARF, transcribed using alternative exons 1 or 1 spliced onto the same exons 2 and 3. Both p16INK4A and p14ARF are capable of inhibiting the cell-cycle progression, albeit in different manner; p16INK4A is phosphorylation of retinoblastoma (pRB) dependent while p14ARF is p53-dependent. In this study, we report the discovery of a novel variant of p16INK4A, termed p16, in a primary T-cell acute lymphoblastic leukemia (T-ALL) patient sample and a neuroblastoma cell line, which was expressed at both the transcriptional and translational levels. Cloning and sequencing of the p16 cDNA revealed that p16 was identical to p16INK4A, except that it contained an in-frame insertion of 197bp between exons 2 and 3. p16 expression was detected in the majority of p16INK4A-expressing primary T-ALL and B-ALL patient samples and other p16INK4A-expressing tumor samples, but was only barely detectable in some normal mononuclear cells and other non-tumor samples. Structural analysis by nuclear magnetic resonance and circular dichroism confirmed that p16, like p16INK4A, is also an ankyrin-repeat protein. Functional analysis of p16 revealed that p16 protein interacted with cyclin D-dependent kinase4 and inhibited its kinase activity. Using a luciferase reporter assay, the transfection of p16 repressed the E2F response, the downstream target of pRB, with an efficacy equivalent to that of p16INK4A. Moreover p16, like p16INK4A, induced cell-cycle arrest at G0/G1, and inhibited cell growth in colony formation assay.
机译：INK4A基因座编码两个肿瘤抑制基因p16INK4A和p14ARF，这些基因是使用剪接在相同外显子2和3上的替代外显子1或1转录的。p16INK4A和p14ARF均能够抑制细胞周期进程，尽管方式不同。 p16INK4A是视网膜母细胞瘤（pRB）依赖的磷酸化，而p14ARF是p53依赖的。在这项研究中，我们报告了在原发性T细胞急性淋巴细胞白血病（T-ALL）患者样品和神经母细胞瘤细胞系中发现了一种称为p16的p16INK4A新型变体，该变体在转录和翻译水平上均表达。 p16 cDNA的克隆和测序表明，p16与p16INK4A相同，不同之处在于它在第2外显子和第3外显子之间框内插入197bp。在大多数表达p16INK4A的原代T-ALL和B-中检测到p16表达。所有患者样品和其他表达p16INK4A的肿瘤样品，但仅在某些正常的单核细胞和其他非肿瘤样品中几乎检测不到。通过核磁共振和圆二色性的结构分析证实，p16与p16INK4A一样，也是一种锚蛋白重复蛋白。对p16的功能分析表明，p16蛋白与细胞周期蛋白D依赖性激酶4相互作用并抑制了其激酶活性。使用萤光素酶报告基因检测，p16的转染抑制了pRB的下游靶点E2F反应，其功效与p16INK4A相当。此外，p16与p16INK4A一样，在G0 / G1诱导细胞周期停滞，并在集落形成试验中抑制细胞生长。

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