The Arf tumor suppressor gene promotes hyaloid vascular regression during mouse eye development.
A key tumor suppressor mechanism that is disrupted frequently in human cancer involves the ARF and p53 genes. In mouse fibroblasts, the Arf gene product responds to abnormal mitogenic signals to activate p53 and trigger either cell cycle arrest or apoptosis. Recent evidence indicates that Arf also has p53-independent functions that may contribute to its tumor suppressor activity. Using Arf(-/-) and p53(-/-) mice, we have discovered a p53-independent requirement for Arf in the developmental regression of the hyaloid vascular system (HVS) in the mouse eye. Arf is expressed in the vitreous of the eye and is induced before HVS regression in the first postnatal week. In the absence of Arf, failed HVS regression causes a pathological process that resembles persistent hyperplastic primary vitreous, a developmental human eye disease thought to have a genetic basis. These findings demonstrate an essential and unexpected role for Arf during mouse eye development, provide insights into the potential genetic basis for persistent hyperplastic primary vitreous, and indicate that Arf regulates vascular regression in a p53-independent manner. The latter finding raises the possibility that Arf may function as a tumor suppressor at least in part by regulating tumor angiogenesis.
McKeller
Robyn N
RN
Department of Hematology/Oncology, Developmental Neurobiology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA.
Fowler
Jennifer L
JL
Cunningham
Justine J
JJ
Warner
Nikita
N
Smeyne
Richard J
RJ
Zindy
Frederique
F
Skapek
Stephen X
SX
D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005123:Eye / Q000098:blood supply* / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D005124:Eye Abnormalities / Q000097:blood / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D019942:Genes, p16 / Q000502:physiology*; D006818:Hyalin / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009024:Morphogenesis; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000502:physiology
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53