It is now established that the degradation of tumour suppressors by oncogenic E3 ligases is a key step during cancer development. One good example of it is the case of the ubiquitin E3 ligase E6-Associted Protein (E6AP). E6AP was initially identified to be recruited by the high-risk human papillomavirus (HPV) to promote the proteasomal degradation of p53, a process that has been implicated in the pathogenesis of human uterine cervical cancer. Furthermore, our lab previously discovered that E6AP is the major E3 ligase of the tumour suppressor PML, an important activator, and a target gene of p53.
To further investigate the relationship between E6AP and p53 we examined the effect of E6AP on a key regulator of p53 apoptotic activity, the ASPP family, which function as tumour suppressors. Deregulation of ASPP proteins levels has been reported in multiple human tumor types, supporting their importance in tumorigenesis, and hence their tight regulation.
Here we demonstrate that E6AP decreases the protein levels of ASPP members and we show that this effect depends on the catalytic activity of E6AP. Importantly, the regulation of ASPP by E6AP is also evidenced by the observation that the levels of ASPP members are altered in multiple tissues derived from E6AP-deficient mice.