Trends in Biochemical Sciences
The INK4a/ARF tumor suppressor: one gene—two products—two pathways
Section snippets
Retinoblastoma protein and p53 in tumor suppression
The prominence of RB, or its functionally linked components, as a target of tumorigenesis relates to its integral role in the regulation of cell-cycle progression, gene transcription and cellular differentiation[5]. RB is best understood in its capacity as the gatekeeper of a key cell-cycle transition, the restriction point (R point), that marks the cell's irreversible commitment to exit from G1 (resting) phase into S (DNA synthetic) phase (Fig. 1)[6]. In normal cycling cells, entry into S
The familial melanoma gene at 9p21
The convergence of the fields of cancer genetics and cell-cycle biochemistry brought the INK4a gene to the forefront of cancer biology. Genetic analyses in familial melanoma kindreds established that there is a strong linkage to a tumor suppressor at the 9p21 chromosomal hot spot (Table 1)[23]. This locus contains the INK4a gene that encodes p16INK4a (also known as MST1 or CDKN2)[24]. The p16INK4a protein, a CKI and founding member of the INK4 family, inhibits the association between CDK4/6 and
The discovery of p19ARF, a potent growth inhibitor encoded by the INK4a/ARF locus
A different debate was ignited by the discovery that a portion of the INK4a gene has the capacity to encode a second growth-inhibitory protein, p19ARF (ARF stands for alternative-reading-frame protein)[31]. This attribute is made possible by a unique gene structure that generates two distinct open reading frames (ORFs) that initiate in different first exons and continue in alternative reading frames in a common second exon31, 32, 33, 34.
This unusual utilization of overlapping exonic sequences
The p19ARF and p53 connection
The initial clue to the p19ARF mechanism of action, and to functional linkage to a specific tumor-suppressor pathway, was provided by the observation that p53 is required for p19ARF-induced G1 arrest[44]. The absence of p53 mutations in Arf−/− mouse embryo fibroblast cultures passaged beyond crisis[44]and in RAS-induced melanomas in Ink4a−/− mice[40]is consistent with this relationship. Furthermore, in cell-culture-based transformation experiments, p19ARF potently suppresses oncogenic
Acknowledgements
We thank Nicole Schreiber-Agus, Liang Zhu, Richard Pestell, Tal Raveh and Glenn Merlino for critical reading of the manuscript. J. P. is a Howard Hughes Medical Institute Medical Student Research Training Fellow. R. A. D is supported by grants from the NIH (NIH grants R01HD28317, R01EY09300 and R01EY11267), as well as the Irma T. Hirschl Award. We also thank the Albert Einstein Cancer Center for support (core grant P30CA13330).
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