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s ATM and DNA PK 81,82 , supporting E3 ligase inhibitor the notion that in response to DNA damage, c Abl and p53 act in a widespread pathway. It has been a matter of debate to what extent p53 and its homolog p73 contribute to c Abl mediated growth inhibition reviewed in 67 . On the a single hand, p53 is essential for c Abl induced cell growth arrest, a approach involving Cdk2 79,83,84 . On the other hand, c Abl induced apoptosis is mostly linked to its cooperation with p73 reviewed in 67 . This cooperation doesn't require p53, and c Abl in mouse fibroblasts can induce apoptosis within the absence of p53. Even though these studies do not suggest the absolute requirement of p53 in c Abl induced apoptosis, it is important to note that c Abl p73 cooperation in apoptosis was achieved by overexpression of both proteins in transient transfection e.
g. 68 , and c Abl induced apoptosis within the absence of p53 was impaired, but not abolished 85,86 . Furthermore, other studies demonstrated cooperation amongst c Abl and p53 within the induction of apoptosis 78 . C Abl enhances the transcriptional E3 ligase inhibitor activity of p53 72,87 and p73 88 . Given that both p73 and p53 are essential for the induction of apoptotic genes 89 , it's likely that c Abl activates both p53 and p73, which work in concert to induce apoptosis in a transcriptional dependent mechanism. As mentioned earlier, p53 also induces apoptosis in a transcriptional independent manner. This cytoplasmic activity of p53 has gained a lot interest lately and is discussed elsewhere in this situation.
In brief, it has been shown that p53 is localized towards the mitochondria Linifanib where it interacts with several mitochondrial proteins, Bcl 2, Bcl Xl, Bak, and Bax, inducing the permeabilization from the mitochondrial membrane and Carcinoid consequently the release of cytochrome C reviewed in 90,91 and Moll in this situation . Intriguingly, in response towards the production of reactive oxygen species ROS c Abl accumulates within the mitochondria imposing the loss of mitochondrial transmembrane potential 92 . Further, in response to ER pressure c Abl shuttles from the ER towards the mitochondria where it triggers cytochrome C release and also the onset of apoptosis 93 . Even though there is no evidence for co localization or interaction amongst p53 and c Abl within the mitochondria, it's tempting to suggest that c Abl and p53 might cooperate in their pro apoptotic mitochondrial effect, in addition to the transcriptional dependent apoptotic pathway.
Mechanisms of c Abl p53 cooperation P53 activation by protein interaction We have shown that physiological levels of c Abl in major mouse cells are essential for sustaining the basal levels from the p53 protein. Much more importantly, c Abl was demonstrated to be essential Linifanib for the maximal and efficient accumulation of p53 in response to DNA damage 94 . Even though p53 and c Abl interact in vitro and in vivo, this interaction is enhanced below pressure circumstances, for example exposure E3 ligase inhibitor to Ara C 1 b D arabinofuranosylcytosine or methylmethanesulfonate MMS 84,95 . This interaction was shown to be necessary for the activation of p53 transcriptional activity. As mentioned above, the binding internet site within c Abl was mapped towards the prolinerich region 72 , whereas in p53 it was defined at the Cterminus within the tetramerization domain residues 325 356 and also the C terminal regulatory domain residues 363 393 95 .
The localization from the c Abl binding internet sites at the p53 C terminus provoked the suggestion that c Abl relieves p53 from its C terminal auto inhibitory domain and locks p53 in an active type, thereby stabilizing the certain interaction of p53 with DNA 95 . However, the contribution of p53 C terminus towards the binding of certain DNA sequences has been lately challenged Linifanib 96 . Interestingly, the C terminus c Abl binding internet site encompasses the region containing the big ubiquitination internet sites of p53 6 lysine residues amongst amino acids 370 and 386; 95,97 . This raises the notion that c Abl might safeguard p53 from degradation by interfering using the ubiquitination of p53 by way of example by masking the lysine target internet sites , thereby top to p53 accumulation as long as c Abl remains attached to p53.
Even though this model is attractive, it should be kept in mind that added mechanisms have been demonstrated see beneath , and that the validity from the p53 c Abl interaction is controversial 98 . It isn't clear if these various interpretations E3 ligase inhibitor represent various experimental program circumstances or indeed reflect a weak interaction amongst c Abl and p53. Activation Linifanib of p53 by neutralizing the inhibitory effects of Mdm2 Given that Mdm2 may be the important inhibitor of p53, it was imperative to ask no matter if c Abl protects p53 from the inhibitory effects of Mdm2. Indeed, c Abl was discovered to neutralize the ability of Mdm2 to both promote the ubiquitination and degradation of p53, and to inhibit its transcriptional and apoptotic activities 87 . As discussed above, low levels of ubiquitination serve as a nuclear export signal for p53 14 . The influence of c Abl on p53 therefore relieves it from Mdm2 suppression and leads