Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest.
The INK4a (MTS1, CDKN2) gene encodes an inhibitor (p16INK4a) of the cyclin D-dependent kinases CDK4 and CDK6 that blocks them from phosphorylating the retinoblastoma protein (pRB) and prevents exit from the G1 phase of the cell cycle. Deletions and mutations involving INK4a occur frequently in cancers, implying that p16INK4a, like pRB, suppresses tumor formation. An unrelated protein (p19ARF) arises in major part from an alternative reading frame of the mouse INK4a gene, and its ectopic expression in the nucleus of rodent fibroblasts induces G1 and G2 phase arrest. Economical reutilization of coding sequences in this manner is practically without precedent in mammalian genomes, and the unitary inheritance of p16INK4a and p19ARF may underlie their dual requirement in cell cycle control.
Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, Tennessee 38101, USA.
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D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D002467:Cell Nucleus / Q000737:chemistry; D003001:Cloning, Molecular; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005091:Exons / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009928:Organ Specificity; D014176:Protein Biosynthesis; D011506:Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D016364:Reading Frames / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D025803:Tumor Suppressor Protein p14ARF
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011506:Proteins; D012333:RNA, Messenger; D025803:Tumor Suppressor Protein p14ARF