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Tumor suppressive activity of prolyl isomerase Pin1 in renal cell carcinoma
Brian L Teng1, Kathryn E Hacker, Shufen Chen
1Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Abstract:
Pin1 specifically recognizes and catalyzes the cis-trans isomerization of phosphorylated-Ser/Thr-Pro bonds, which modulate the stability, localization, and function of numerous Pin1 targets involved in tumor progression. However, the role of Pin1 in cancer remains enigmatic as the gene is located on chromosome 19p13.2, which is a region subject to loss of heterozygosity in several tumors. Since Pin1 protein is frequently under-expressed in kidney cancer, we have explored its role in human clear cell renal cell carcinoma (ccRCC). Here we show evidence for PIN1 gene deletion and mRNA under-expression as a mechanism of Pin1 reduction in ccRCC tumors. We demonstrate that restoration of Pin1 in cell lines found to be deficient in Pin1 protein expression can attenuate the growth of ccRCC cells in soft agar and a xenograft tumor model. Moreover, this ability of Pin1 to negatively influence tumor growth in ccRCC cells may be dependent on the presence of functional p53, which is infrequently mutated in ccRCC. These observations suggest Pin1 may have a mild tumor suppressive role in ccRCC.
Insights
Pin1 protein under-expression, potentially due to gene deletion, was observed in clear cell renal cell carcinoma (ccRCC). Restoring Pin1 suppressed ccRCC tumor growth, suggesting a mild tumor suppressive role.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Pin1 (Peptidyl-prolyl cis-trans isomerase) targets phosphorylated Ser/Thr-Pro bonds, influencing protein stability and function in tumor progression.
- The role of Pin1 in cancer is complex, with its gene located on chromosome 19p13.2, a region prone to loss of heterozygosity.
- Pin1 protein is notably under-expressed in kidney cancer, prompting investigation into its specific role in clear cell renal cell carcinoma (ccRCC).
Purpose of the Study:
- To investigate the role of Pin1 in human clear cell renal cell carcinoma (ccRCC).
- To determine the mechanisms underlying Pin1 reduction in ccRCC tumors.
- To assess the impact of Pin1 restoration on ccRCC cell growth and tumor development.
Main Methods:
- Analysis of PIN1 gene deletion and mRNA expression in ccRCC tumors.
- Restoration of Pin1 expression in ccRCC cell lines deficient in Pin1.
- Assessment of ccRCC cell growth in soft agar and a xenograft tumor model following Pin1 restoration.
- Evaluation of the dependency of Pin1's tumor-suppressive effect on functional p53.
Main Results:
- Evidence of PIN1 gene deletion and mRNA under-expression contributing to reduced Pin1 levels in ccRCC.
- Restoration of Pin1 significantly attenuated ccRCC cell growth in vitro (soft agar) and in vivo (xenograft model).
- The tumor-suppressive function of Pin1 in ccRCC appears to be dependent on the presence of functional p53.
Conclusions:
- Pin1 reduction in ccRCC can occur via gene deletion and mRNA under-expression.
- Restoring Pin1 expression inhibits ccRCC tumor growth, indicating a potential tumor suppressive role.
- Pin1's tumor suppressive function in ccRCC may be linked to functional p53 status.
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