title: Losses of both products of the Cdkn2a/Arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis.
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.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Altomare
authors.forename: Craig W
authors.initials: CW
authors.lastname: Menges
authors.forename: Jinfei
authors.initials: J
authors.lastname: Xu
authors.forename: Jianming
authors.initials: J
authors.lastname: Pei
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Ara
authors.initials: A
authors.lastname: Tadevosyan
authors.forename: Erin
authors.initials: E
authors.lastname: Neumann-Domer
authors.forename: Zemin
authors.initials: Z
authors.lastname: Liu
authors.forename: Michele
authors.initials: M
authors.lastname: Carbone
authors.forename: Ilse
authors.initials: I
authors.lastname: Chudoba
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
mesh_terms: D000483:Alleles; D000818:Animals; D001194:Asbestos / Q000009:adverse effects*; D033481:Chromosomes, Mammalian / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency* / Q000378:metabolism; D020868:Gene Silencing; D056426:Genetic Loci / Q000235:genetics*; D006801:Humans; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency* / Q000378:metabolism
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D001194:Asbestos