MDM2 can mediate the degradation of tumor suppressor p53 through an autoregulatory feedback loop, in which MDM2 abolishes wild-type p53 function and accelerates malignant transformation.
The MDM2 homolog MDMX oncoprotein is indispensable for inhibition of p53 during normal embryonic development and malignant transformation, yet how MDMX harnesses p53 functions is unclear.
Indeed, a large body of work has shown that dysregulation of p53 and its E3 ligase MDM2 by the ubiquitin-proteasome system (UPS) promotes carcinogenesis and malignant transformation.
We also examined TP53 and MDM2 protein immunohistochemistry (IHC) to assess the involvement of these differences in malignant transformation and disease progression.
The results demonstrated overexpression of important proteins (p53 and MDM2) related to regulatory mechanisms of apoptosis in OLP, suggesting that there is a favorable environment for malignant transformation.
Collectively, our results identify HMGA2 and MDM2 as amplification targets in PA and Ca-ex-PA and suggest that amplification of 12q genes (in particular MDM2), deletions of 5q23.2-q31.2, gains of 8q12.1 (PLAG1) and 8q22.1-q24.1 (MYC), and amplification of ERBB2 may be of importance for malignant transformation of benign PA.
Together, our data suggests that arsenic compounds predispose cells to malignant transformation by up-regulation of Hdm2 and subsequent p53 inactivation.
Our findings show that p53, Bax, Bcl-2 and Mdm2 mRNA expression levels correlate with the malignant transformation of the uterine cervix. mRNA coexpression patterns of the members of the pro- and anti-apoptotic family examined in cervical carcinogenesis were found to be disrupted in CIN and cancer, as already demonstrated at the protein level.
Elevated expression of p53, MDM2, and p14(ARF) in benign and malignant ameloblastomas suggests that alteration of the p53-MDM2-p14(ARF) cascade is involved in oncogenesis and/of malignant transformation of odontogenic epithelium. p53 gene status implied that p53 mutation might play a minor role in neoplastic changes of odontogenic epithelium.
These findings suggest that amplification and overexpression of HMGIC and possibly MDM2 might be important genetic events that may contribute to malignant transformation of benign PA.