leomorphic salivary A
ene 1) and PLAGL2 (PLAG1-like 2) are oncogenes involved in various malignancies. Dysregulated PLAG1 expression due to chromosomal translocation is crucial in the formation of pleomorphic adenomas of the salivary glands[1
] and other tumors[2
]. PLAG1 overexpression is also detected in tumors without chromosomal translocation, such as uterine leiomyomas, leiomyosarcomas, and smooth muscle tumors[5
]. PLAGL2 is similar to PLAG1 structurally and functionally, and both have been implicated in the pathogenesis of acute myeloid leukemia[6
]. Similar to PLAG1, PLAGL2 is a transcription factor with a DNA-binding and a transactivation domain [8
]. However, besides its role in transcription , other functions of PLAGL2 are not well-studied.
P53 is important in coordinating cellular responses to stress[10
]. Given its critical role, it is not surprising that p53 is tightly regulated by post-translational modifications, including ubiquitination[12
]. There are several cellular ubiquitination E3 ligases for p53, and their activities are regulated by protein-protein interactions or post-translational modifications. The best studied p53 E3 ligase is Mdm2. If activated in certain malignancies, Mdm2 is able to abolish the tumor suppressor function of p53. There are various regulatory mechanisms to modulate Mdm2 functions. Mdm2 enzymatic activity is inhibited by its association with p19ARF
], ribosomal protein L11 [14
] or TSG101 [15
], while enhanced by interacting with MTBP[16
] or YY1[17
]. Post-translational modification, such as phosphorylation by Ataxia Telangiectasia-mutated (ATM) in response to DNA damage, also regulates Mdm2-p53 interaction[18
]. Other E3 ubiquitination enzymes for p53 are E6-AP [19
], COP1 [20
] and Pirh2 [22
]. Among them, Pirh2 is a target gene of p53; its transcript and protein levels increase in response to UV irradiation and cisplatin treatment [22
]. A recent study showed that Porcine Circovirus type 2 (PCV2) ORF3 protein interacts with Pirh2 and regulates its stability [23
]. Despite its importance as a p53 ubiquitination E3 ligase, little is known about how Pirh2 is regulated by cellular factors.
In our study, we found that PLAGL2 interacts with Pirh2 dimers, resulting in its stabilization. This study not only identifies a novel regulatory mechanism for Pirh2, but also provides a mechanistic explanation for PLAGL2’s role as an oncoprotein.