Involvement of the INK4a/Arf gene locus in senescence.
The INK4a/ARF locus encodes two proteins whose expression limits cellular proliferation. Whilst the biochemical activities of the two proteins appear very different, they both converge on regulating the retinoblastoma and p53 tumour suppressor pathways. Neither protein is required for normal development, but lack of either predisposes to the development of malignancy. Both proteins have also been implicated in the establishment of senescence states in response to a variety of stresses, signalling imbalances and telomere shortening. The INK4a/Arf regulatory circuits appear to be partially redundant and show evidence of rapid evolution. Especially intriguing are the large number of biological differences documented between mice and man. We review here the brief history of INK4a/Arf and explore possible links with organismal aging and the evolution of longevity.
Collins
Carol J
CJ
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
Sedivy
John M
JM
D000818:Animals; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D006801:Humans; D008957:Models, Genetic; D016160:Retinoblastoma Protein / Q000235:genetics / Q000502:physiology; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53