Upon DNA damage, stress-related signals or oncogenic stimulus, this pathway is activated. E2F1 induces the transcription of components of the apoptosis pathway such as p53, ATM, CHEK2 and p14ARF. When a problem occurs, p14ARF is able to block the cell cycle in G1 by binding to E2F1 and DP1 independently and sequestering them in the nucleolus until damage is repaired (Datta et al., 2002; Datta et al., 2005). Similarly, p14ARF can sequester MDM2 in the nucleolus and prevent the binding with p53 (Tannapfel et al., 2002). The role of MDM2 is to keep p53 level low by sequestering and hiding domains on p53 protein that are responsible for its transcriptional activity. Moreover, MDM2 binds to and promotes p53 nuclear export and its subsequent ubiquitin-proteasome degradation in the cytoplasm (Freedman and Levine, 1998; Fuchs et al., 1998; Honda et al., 1997).
On one hand, Akt1 participates in keeping p53 activity down by phosphorylating MDM2, which increases its affinity with p53 (Chaussepied and Ginsberg, 2004), and on the other hand, ATM-regulated phosphorylation of MDM2 diminishes the binding of the two proteins. Similarly, multiple phosphorylations of p53 by ATM (in case of DNA double-strand break), ATR (other types of damage) and CHEK1 and 2 stabilize p53 protein by hiding the binding site of MDM2 (Powers et al., 2004).
ATM is active when phosphorylated and in complex with NBS1 (Vermeulen et al., 2003). The auto-phosphorylation of ATM at Ser-1981 is catalyzed by E2F1 (Rogoff et al., 2004). Both ATM and ATR participate in the phosphorylation of E2F1 (Dimova and Dyson, 2005) which facilitates its interaction with 14-3-3 tau and as a result, the induction of E2F1 apoptotic targets including Apaf-1 and the caspases responsible for the activation of apoptosis (Wang et al., 2004). The cell cycle can be arrested later with the phosphorylation by CHEK1 and 2 of important proteins such as CDC25C that intervenes at the G2/M transition (Castedo et al., 2002).
The apoptosis entry module describes the regulation network around p53 activity but does not treat downstream activation of apoptosis. When p53 level is high, the cell cycle arrests (by mediating transcription of the cyclin-dependent kinase inhibitor p21CIP1, for example) and waits for DNA to be repaired. If the repair takes too long, apoptosis is activated. The pathway, as it is in this diagram, is incomplete. We plan to extend the description of the intrinsic pathway of apoptosis in future works.
Using techniques of structural analysis, it is possible to isolate cycles from this module. Here, only one was obtained and involves MDM2 and p53.
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