Losses of both products of the Cdkn2a/Arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis.
Losses of both products of the Cdkn2a/Arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis.
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DOI：
10.1371/journal.pone.0018828
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发表时间：
2011-04-19
期刊：
影响因子：
3.7
通讯作者：
Testa JR
中科院分区：
文献类型：
--
作者：
Altomare DA;Menges CW;Xu J;Pei J;Zhang L;Tadevosyan A;Neumann-Domer E;Liu Z;Carbone M;Chudoba I;Klein-Szanto AJ;Testa JR
CDKN 2A/ARF基因座包括重叠的肿瘤抑制基因p16（INK 4A）和p14（ARF），它们在人类恶性间皮瘤（MM）中经常共缺失。p16（INK 4A）缺失在人类癌症中的重要性已经得到了很好的证实，但p14（ARF）缺失的相对重要性一直存在争议。由于分别靶向外显子1α或1β，单独缺乏Ink 4a或Arf的小鼠的肿瘤易感性支持了这两种基因在抑制自发性肿瘤中发挥重要且非冗余作用的观点。为了进一步验证这一概念，我们将Ink 4a（+/−）和Arf（+/−）小鼠暴露于石棉，石棉是MM的主要原因。石棉处理的Ink 4a（+/−）和Arf（+/−）小鼠显示出相对于野生型同窝小鼠MM的发病率增加和潜伏期缩短。来自Ink 4a（+/-）小鼠的p53表现出Ink 4a的双等位基因失活、Arf或p53表达的缺失以及p15（Ink 4 b）的频繁缺失。相反，来自Arf（+/-）小鼠的cDNA表现出Arf表达的缺失，但不需要Ink 4a或Ink 4 b的缺失。由于Cdkn 2a/Arf外显子2缺失，Ink 4a和Arf双缺陷小鼠相对于单独Ink 4a或Arf缺陷小鼠表现出加速石棉诱导的MM形成，并且CD 34表现出两种肿瘤抑制基因的双等位基因缺失。在MM中，Arf的肿瘤抑制功能是p53非依赖性的，因为Arf缺失的MM保留了功能性p53。总的来说，这些体内数据表明，CDKN 2A/ARF基因产物抑制石棉致癌性。此外，虽然Arf的失活似乎对MM发病机制至关重要，但p16（Ink 4a）和p19（Arf）的失活协同加速石棉诱导的肿瘤发生。
The CDKN2A/ARF locus encompasses overlapping tumor suppressor genes p16(INK4A) and p14(ARF), which are frequently co-deleted in human malignant mesothelioma (MM). The importance of p16(INK4A) loss in human cancer is well established, but the relative significance of p14(ARF) loss has been debated. The tumor predisposition of mice singly deficient for either Ink4a or Arf, due to targeting of exons 1α or 1β, respectively, supports the idea that both play significant and nonredundant roles in suppressing spontaneous tumors. To further test this notion, we exposed Ink4a(+/−) and Arf(+/−) mice to asbestos, the major cause of MM. Asbestos-treated Ink4a(+/−) and Arf(+/−) mice showed increased incidence and shorter latency of MM relative to wild-type littermates. MMs from Ink4a(+/−) mice exhibited biallelic inactivation of Ink4a, loss of Arf or p53 expression and frequent loss of p15(Ink4b). In contrast, MMs from Arf(+/−) mice exhibited loss of Arf expression, but did not require loss of Ink4a or Ink4b. Mice doubly deficient for Ink4a and Arf, due to deletion of Cdkn2a/Arf exon 2, showed accelerated asbestos-induced MM formation relative to mice deficient for Ink4a or Arf alone, and MMs exhibited biallelic loss of both tumor suppressor genes. The tumor suppressor function of Arf in MM was p53-independent, since MMs with loss of Arf retained functional p53. Collectively, these in vivo data indicate that both CDKN2A/ARF gene products suppress asbestos carcinogenicity. Furthermore, while inactivation of Arf appears to be crucial for MM pathogenesis, the inactivation of both p16(Ink4a) and p19(Arf) cooperate to accelerate asbestos-induced tumorigenesis.
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影响因子：
50.3
作者：
Jongsma, Johan;van Montfort, Erwin;Berns, Anton
通讯作者：
Berns, Anton
DOI：
10.1165/rcmb.2009-0206tr
发表时间：
2010-02-01
影响因子：
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作者：
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通讯作者：
Mossman, Brooke T.
影响因子：
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作者：
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64.5
作者：
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Sharpless, NE;Ramsey, MR;DePinho, RA
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