Figure 5.7. Role of the p19ARF protein in checkpoint control.

Figure 5.7

Role of the p19ARF protein in checkpoint control. The p19ARF protein (ARF) responds to proliferative signals normally required for cell proliferation. When these signals exceed a critical threshold, the ARF-dependent checkpoint (vertical barrel) is activated, and ARF triggers a p53-dependent response that induces growth arrest and/or apoptosis. Signals now known to induce signaling via the ARF-p53 pathway include Myc, E1A, and E2F-1. In principle, ‘upstream’ oncoproteins, such as products of mutated Ras alleles, constitutively activated receptors, or cytoplasmic signal transducing oncoproteins, might also trigger ARF activity via the cyclin D-cdk4-Rb-E2F or Myc-dependent pathways, both of which are normally necessary for S-phase entry. In inhibiting cyclin D-dependent kinases, p16INK4a can dampen the activity of mitogenic signals. In the figure, E1A is shown to work, at least in part, by opposing Rb function. For simplicity, Myc and E2F-1 are only shown to activate p53 via the effects on ARF, though highly overexpressed levels of these proteins can activate p53 in ARF-negative cells, albeit with an attenuated efficiency. ARF activation of p53 likely depends on inactivation of Mdm2-specific function(s). DNA damage signals (e.g., ionizing and UV radiation, hypoxic stress, etc.) activate p53 through multiple signaling pathways. [The figure corresponds to Figure 1 of Sherr CJ. Tumor surveillance via the ARF-p53 pathway. Genes & Development 12:2984-2991, 1998.].

From: Chapter 5, Tumor Suppressor Gene Defects in Human Cancer

Cover of Holland-Frei Cancer Medicine
Holland-Frei Cancer Medicine. 5th edition.
Bast RC Jr, Kufe DW, Pollock RE, et al., editors.
Hamilton (ON): BC Decker; 2000.
© 2000, BC Decker Inc.

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