Regulation of the MDM2‐p53 pathway by the ubiquitin ligase HERC2

Abstract

The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53-response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53-MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.

Pro-Oxidant Therapeutic Activities of Cerium Oxide Nanoparticles in Colorectal Carcinoma Cells

“…In cytoplasm, the activity of p53 is masked through the inhibitory action of Mdm2 which act as a negative regulator and functions as a ubiquitin ligase. 37 Upon DNA damage, phosphorylation of p53 disrupts the Mdm2 binding, and the inhibitory masking is withdrawn following the nuclear translocation. 38 In particular, p53 enhances p21 transcription in the nucleus, which in turn inhibits cyclin-dependent kinase activity followed by the prevention of pRb from derepressing E2F1 which suppress the progression from G1 to S phase.…”

HERC Ubiquitin Ligases in Cancer

“…MDM2 is one such gene whose promoter competes with HERC2 for binding of oligomeric, phosphorylated, and acetylated p53. As its gene expression increases MDM2 protein levels, these can bind p53 and restart the regulatory loop ( Figure 3) [68]. These findings highlight the importance of HERC2 in regulating the transcriptional program of the tumor suppressor protein p53.…”

Long Non-Coding RNA BC040587 is Required in Cell Invasion of Renal Cancer Induced by Acidosis

“…Among them, MDM2 was the most attractive one. MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4 [14]. Activation of either AKT or ERK can induce both phosphorylation of MDM2 and enhancement of the fundamental interaction between MDM2 and p53 [20].…”

“…Moreover, dysregulation of BC040587 expression could be a critical step in sarcoma, suggesting an example in tumorigenesis [12] MDM2/P53 negative feedback pathway is notable in cancer research, and it is mainly related to apoptosis as well as proliferation [13]. MDM2 is considered as a notable inhibitor of P53, and its combination with P53 can degrade P53 protein, leading to inactivity of P53 [14]. MDM2 is frequently altered in solid tumors of stomach [15], lung [16] as well as breast [17].…”