VprBP/DCAF1 regulates p53 function and stability through site-specific phosphorylation

Abstract

VprBP (also known as DCAF1) is a recently identified kinase that is overexpressed in cancer cells and serves as a major determinant for epigenetic gene silencing and tumorigenesis. The role of VprBP in driving target gene inactivation has been largely attributed to its ability to mediate histone H2A phosphorylation. However, whether VprBP also phosphorylates non-histone proteins and whether these phosphorylation events drive oncogenic signaling pathways have not been explored. Here we report that serine 367 phosphorylation (S367p) of p53 by VprBP is a key player in attenuating p53 transcriptional and growth suppressive activities. VprBP catalyzes p53S367p through a direct interaction with the C-terminal domain of p53. Mechanistically, VprBP-mediated S367p inhibits p53 function in the wake of promoting p53 proteasomal degradation, because blocking p53S367p increases p53 protein levels, thereby enhancing p53 transactivation. Furthermore, abrogation of VprBP-p53 interaction by p53 acetylation is critical for preventing p53S367p and potentiating p53 function in response to DNA damage. Together, our findings establish VprBP-mediated S367p as a negative regulator of p53 function and identify a previously uncharacterized mechanism by which S367p modulates p53 stability.

DCAF1 promotes gastric cancer progression by PI3K/AKT/mTOR pathway

“…Kim et al 33 identi ed that the LisH motif of DCAF1 is a negative regulator of p53, and knocking down DCAF1 leads to the activation of p53 target genes. In addition, DCAF1 weakened the p53 tumor inhibition pathway and accelerated cancer development by phosphorylating the serine 367 of p53 (S367p) 34 . Our results indicated that DCAF1 enhances the progression of GC through the activation of the PI3K/AKT/mTOR pathway.…”

Glucose deprivation triggers DCAF1-mediated inactivation of Rheb-mTORC1 and promotes cancer cell survival

“…Silencing DCAF1 resulted in defective progression through S phase, inhibited cell proliferation, triggered apoptosis, and led to early embryonic lethality [ 25 ]. Additionally, several reports have revealed that DCAF1 is involved in the development of tumors and other diseases [ 22 , 26 – 30 ]. Most recently, DCAF1 was further developed as an attractive target for the development of targeted protein degraders [ 31 – 33 ].…”

Pentylenetetrazole-Induced Seizures Are Increased after Kindling, Exhibiting Vitamin-Responsive Correlations to the Post-Seizures Behavior, Amino Acids Metabolism and Key Metabolic Regulators in the Rat Brain

“…Mutual regulation of these fluxes depends on transcriptional factor p53, a master regula-tor of energy metabolism, that is known to control perturbations of neuronal activity, particularly in epileptic seizures and upon kindling [30][31][32][33][34]. In its turn, such PTM as phosphorylation strongly regulates the function and stability of p53 [35][36][37][38]. However, specific significance of the p53 phosphorylation in epilepsy is not studied as extensively as it is in cancer [35,37].…”

“…In its turn, such PTM as phosphorylation strongly regulates the function and stability of p53 [35][36][37][38]. However, specific significance of the p53 phosphorylation in epilepsy is not studied as extensively as it is in cancer [35,37].…”