p19Arf suppresses growth, progression, and metastasis of Hras-driven carcinomas through p53-dependent and -independent pathways.
Ectopic expression of oncogenes such as Ras induces expression of p19(Arf), which, in turn, activates p53 and growth arrest. Here, we used a multistage model of squamous cell carcinoma development to investigate the functional interactions between Ras, p19(Arf), and p53 during tumor progression in the mouse. Skin tumors were induced in wild-type, p19(Arf)-deficient, and p53-deficient mice using the DMBA/TPA two-step protocol. Activating mutations in Hras were detected in all papillomas and carcinomas examined, regardless of genotype. Relative to wild-type mice, the growth rate of papillomas was greater in p19(Arf)-deficient mice, and reduced in p53-deficient mice. Malignant conversion of papillomas to squamous cell carcinomas, as well as metastasis to lymph nodes and lungs, was markedly accelerated in both p19 (Arf)- and p53-deficient mice. Thus, p19(Arf) inhibits the growth rate of tumors in a p53-independent manner. Through its regulation of p53, p19(Arf) also suppresses malignant conversion and metastasis. p53 expression was upregulated in papillomas from wild-type but not p19( Arf)-null mice, and p53 mutations were more frequently seen in wild-type than in p19( Arf)-null carcinomas. This indicates that selection for p53 mutations is a direct result of signaling from the initiating oncogenic lesion, Hras, acting through p19(Arf).
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Karen S
KS
Kelly-Spratt
Kay E
KE
Gurley
Yutaka
Y
Yasui
Christopher J
CJ
Kemp
D015127:9,10-Dimethyl-1,2-benzanthracene; D000483:Alleles; D000818:Animals; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D003433:Crosses, Genetic; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018450:Disease Progression; D011905:Genes, ras; D005838:Genotype; D019656:Loss of Heterozygosity; D008207:Lymphatic Metastasis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics; D010212:Papilloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
D002273:Carcinogens; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene; D016283:Proto-Oncogene Proteins p21(ras)