| First Author | Valbuena A | Year | 2008 |
| Journal | PLoS One | Volume | 3 |
| Issue | 7 | Pages | e2649 |
| PubMed ID | 18612383 | Mgi Jnum | J:172966 |
| Mgi Id | MGI:5009379 | Doi | 10.1371/journal.pone.0002649 |
| Citation | Valbuena A, et al. (2008) The C/H3 domain of p300 is required to protect VRK1 and VRK2 from their downregulation induced by p53. PLoS One 3(7):e2649 |
| abstractText | BACKGROUND: The vaccinia-related kinase 1 (VRK1) protein, an activator of p53, can be proteolytically downregulated by an indirect mechanism, which requires p53-dependent transcription. PRINCIPAL FINDINGS: In this work we have biochemically characterized the contribution of several p53 transcriptional cofactors with acetyl transferase activity to the induction of VRK1 downregulation that was used as a functional assay. Downregulation of VRK1 induced by p53 is prevented in a dose dependent manner by either p300 or CBP, but not by PCAF, used as transcriptional co-activators, suggesting that p53 has a different specificity depending on the relative level of these transcriptional cofactors. This inhibition does not require p53 acetylation, since a p53 acetylation mutant also induces VRK1 downregulation. PCAF can not revert the VRK1 protection effect of p300, indicating that these two proteins do not compete for a common factor needed to induce VRK1 downregulation. The protective effect is also induced by the C/H3 domain of p300, a region implicated in binding to several transcription factors and SV40 large T antigen; but the protective effect is lost when a mutant C/H3Del33 is used. The protective effect is a consequence of direct binding of the C/H3 domain to the transactivation domain of p53. A similar downregulatory effect can also be detected with VRK2 protein. CONCLUSIONS/SIGNIFICANCE: Specific p53-dependent effects are determined by the availability and ratios of its transcriptional cofactors. Specifically, the downregulation of VRK1/VRK2 protein levels, as a consequence of p53 accumulation, is thus dependent on the levels of the p300/CBP protein available for transcriptional complexes, since in this context this cofactor functions as a repressor of the effect. These observations point to the relevance of knowing the cofactor levels in order to determine one effect or another. |
