Abnormal Expression of MDM2 in Prostate Carcinoma

Abstract

Mutation of p53 is rare in localized prostate carcinoma. The oncoprotein MDM2, whose gene has a response element for p53, promotes the degradation of p53 protein and inhibits its transcriptional activation of genes related to cell cycle arrest and apoptosis, constituting a negative feedback control. We studied p53 and MDM2 expression by immunohistochemistry and looked for mutations in p53 exons 5 to 8 by polymerase chain reaction-single strand conformational polymorphism in 118 patients submitted to radical prostatectomy for localized prostate cancer. In 28 cases, we studied cell proliferation by immunohistochemistry, using antibody for Ki-67, and apoptosis by the deoxynucleotidyl transferase mediated dUTP biotin nick end labeling technique. Although no p53 mutations were found, p53 protein was detected in 31.4% of the cases, and these cases had higher Gleason scores (P ‫؍‬ .03) and more advanced tumor stages (P ‫؍‬ .02). MDM2 was overexpressed in 40.7% of the cases, and these cases had greater tumor volumes (P ‫؍‬ .001). Tumors that were positive for both p53 and MDM2 were larger (P ‫؍‬ .003) and of more advanced stage (P ‫؍‬ .03). Within the 28-case subset, the proliferative index was higher among MDM2-positive tumors (P ‫؍‬ .046), and the apoptotic index was lower among p53-positive tumors (P ‫؍‬ .01). We conclude that, although p53 mutation is a rare event in prostate carcinogenesis, the detection of p53 protein by immunohistochemistry is common and is associated with decreased apoptosis and increased histologic grade and tumor stage. We also conclude that the overexpression of MDM2 has a role in prostate carcinogenesis, being frequently detected and associated with increased cell proliferation and tumor volume. Finally, we propose that the MDM2-positive/p53-positive phenotype identifies prostate cancers with aggressive behavior.

Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome

“…Deletion or hypermethylation also represents a potential mechanism of removal of the p14ARF protein in a small proportion (16%) of prostate cancers (Konishi et al, 2002). Mutation and altered expression of other upstream regulators of pRB such as p53, p21 and MDM2 (Gao et al, 1995;Osman et al, 1999;Leite et al, 2001) have also been observed in prostate cancer, although mutations in the p53 gene are most frequently associated with metastatic and hormone-refractory disease (Heidenberg et al, 1995). It is particularly significant that prostate cancer exhibits both downregulation of pRB (Brooks et al, 1995;Theodorescu et al, 1997) and overexpression of E2F3.…”

Ubiquitin E3 ligase WWP1 as an oncogenic factor in human prostate cancer

“…Many E3 ubiquitin ligases in the UPP have been implicated in cell cycle control and uncontrolled cell proliferation. Some E3 ligases such as MDM2 and SKP2, which target p53 and CDKN1A/CDKN1B, are considered oncoproteins (Leite et al, 2001;Lu et al, 2002;Drobnjak et al, 2003), while some other E3 ligases are considered tumor suppressors. WWP1 is an E3 ubiquitin ligase that contains four tandem WW domains and a HECT domain.…”

Perturbation of cell cycle regulators in Peyronie’s disease

“…Interestingly, p21 was detected in the control cells, suggesting that there are p53-independent mechanisms involved in the regulation of p21 expression as has been suggested elsewhere. 19 Furthermore, our data indicate that foreskin fibroblasts respond to irradiation in an expected fashion, indicating normal function of the p53 pathway. 20 In these cells, levels of p53 increased dramatically following 5 Gy irradiation from an undetectable level at baseline (Figure 4).…”

“…14 -16 In the normal state, the detection of the p53 protein is difficult due to its very short half-life. 13 Furthermore, p53 does not act in isolation but is under negative feedback control through the action of a variety of downstream elements, two of which are mdm-2 and p21 19 (Figure 1). One of the classic techniques to determine the functional status of the p53 protein is to expose the cells to sub-lethal DNA damage, as occurs with radiation, and to then assess p53 levels.…”