Human tumor suppressor ARF impedes S-phase progression independent of p53.
Using alternative reading frames, the human ARF-INK4a locus encodes two unrelated proteins that both function in tumor suppression. p16(INK4a) maintains the retinoblastoma protein in its growth-suppressive state through inhibition of cyclin D-dependent kinase activity, whereas ARF binds with MDM2 and stabilizes p53. The majority of the activity of ARF to date is ascribed to its ability to activate p53, resulting in a G(1) cell cycle arrest or apoptosis. We show here that ARF colocalizes with DNA replication protein A (RPA32) and that overexpression of ARF reduces the rate of DNA synthesis resulting in accumulation of an S-phase cell population. Impediment of DNA synthesis by ARF can occur and becomes more evident in the absence of p53. Hence, the biological consequence of ARF induction varies dependent on cellular p53 status, inducing predominantly a G(1) arrest or apoptosis in p53-positive cells or causing S-phase retardation when p53 function is comprised.
Yarbrough
Wendell G
WG
Lineberger Comprehensive Cancer Center, Department of Otolaryngology/Head and Neck Surgery, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-3280, USA.
Bessho
Mika
M
Zanation
Adam
A
Bisi
John E
JE
Xiong
Yue
Y
D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051716:Replication Protein A; D016196:S Phase / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C497167:RPA1 protein, human; D051716:Replication Protein A; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins