Abstract
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.
Highlights
CDKN2A/ARF is among the most commonly mutated loci in human cancer, encoding two different tumor suppressors translated from alternatively spliced mRNAs. p16(INK4A) is composed of exons 1a, 2 and 3, and is designated here as INK4A
Previous studies have shown that Arf(2/2) and Ink4a(2/2) mice are more prone to spontaneous tumors than wild-type animals, but each less so than Ink4a;Arf(2/2) mice [8]
The in vivo carcinogenesis studies reported here evaluated the contribution of heterozygous mutations of Arf and Ink4a, as well as a both tumor suppressor genes, to the induction of MM by asbestos, a wellestablished cause of this malignancy
Summary
CDKN2A/ARF is among the most commonly mutated loci in human cancer, encoding two different tumor suppressors translated from alternatively spliced mRNAs. p16(INK4A) is composed of exons 1a, 2 and 3, and is designated here as INK4A (inhibitor of cyclin dependent kinase 4). Knockout mice with targeted deletion of specific Cdkn2A/Arf exons have disrupted p16Ink4a, p19Arf or both genes [1,2,3,4] and develop a different spectrum of spontaneous tumors, not malignant mesotheliomas (MMs). The studies presented here provide genetic evidence for the significance of Ink4a and Arf alterations in MM by directly comparing susceptibility to tumor induction by asbestos in Ink4adeficient, Arf-deficient and doubly heterozygous Ink4a;Arf mice in a common genetic background. The fact that mice deficient for both tumor suppressors have accelerated tumor development indicates that inactivation of both p16(Ink4a) and p19(Arf) cooperate to promote asbestos carcinogenicity
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