Expression of Pirh2, a Newly Identified Ubiquitin Protein Ligase, in Lung Cancer

Abstract

Maintenance of p53 function is important for normal cell growth and development, and loss of p53 function contributes directly to malignant tumor development. The recently discovered Pirh2 protein is an ubiquitin-protein ligase that negatively regulates p53 through activity by targeting it for degradation. To determine how Pirh2 may mediate lung tumorigenesis, we evaluated Pirh2 expression in human and mouse lung tumor samples and paired normal lung tissues using immunoblot analysis and immunohistochemistry. Pirh2 protein expression was higher in 27 (84%) of 32 human lung neoplasms than in matched normal lung tissue and in 14 of 15 mouse lung tumors evaluated. In addition, p53 protein was more ubiquitinated in the mouse lung tumors than in normal tissue, and overall p53 expression was lower than that in normal tissue. These results are consistent with the hypothesis that increased Pirh2 expression affects lung tumorigenesis by reducing p53 activity. To our knowledge, this is the first description of altered Pirh2 expression in human and mouse tumors.

p53‐induced RING‐H2 protein, a novel marker for poor survival in hepatocellular carcinoma after hepatic resection

“…20 Given the importance of p53 as a tumor suppressor, [29][30][31][32][33][34][35][36][37] degradation of p53 would implicate a role for PIRH2 in carcinogenesis and in the development of cancer. Previous studies revealed that the PIRH2 gene is overexpressed in lung cancer and prostate cancer 24,25 ; however, the correlation between its expression and patient prognosis has not been documented, and the expression profile and function of PIRH2 in HCC currently remain unknown. We hypothesized that overexpression of PIRH2 plays a potential role in the development of cancer, and it may be a novel prognostic marker for HCC.…”

“…The intensity of cytoplasmic staining was scored from 0 to 3þ by comparing it with the intensity in positive controls, as described previously. 24,27 The intensity of PIRH2 protein staining in HCC specimens was classified using the following 4-point scale: 0, 10% positive cells; 1þ, 11% to 25% positive cells; 2þ, 26% to 50% positive cells; and 3þ, !51% positive cells. The expression levels of PIRH2 protein, thus, were divided into low expression (0 or 1þ) and high expression (2þor 3þ).…”

“…22,23 It is noteworthy that, in recent studies, the PIRH2 gene was overexpressed in lung cancer and prostate cancer, and overexpression of PIRH2 plays a potential role in the development of cancer. 24,25 However, the expression profile and function of PIRH2 in HCC currently remains unknown. In the current study, we sought to determine the expression level of PIRH2 in HCC and analyzed the correlation between PIRH2 expression and clinicopathologic characteristics.…”

Identification and Characterization of Two Novel Isoforms of Pirh2 Ubiquitin Ligase That Negatively Regulate p53 Independent of RING Finger Domains

“…Emerging as another important player in p53 inactivation and in tumorigenesis is the E3 ligase Pirh2 (11). Like MDM2, Pirh2 is overexpressed in primary tumors (23,24) and therefore, through p53 inhibition, may very well have oncogenic potential. In contrast to MDM2, however, very little is known about Pirh2 structure and function.…”

Ubiquitylation of ε-COP by PIRH2 and regulation of the secretion of PSA

“…Previous studies demonstrated that PIRH2 interacts with several proteins that are involved in cell proliferation and gene activation [5,8,10,35] and that PIRH2 is highly expressed in human non-small cell lung cancer and prostate cancer [10,36]. It is difficult to reconcile the interaction between PIRH2 and -COP with the proliferation by PIRH2.…”