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.
Highlights
Pin1 is a conserved peptidyl-prolyl isomerase that recognizes phosphorylated serine/threonine-proline motifs (Yaffe et al, 1997)
To further examine the role of Pin1 in tumor growth, ACHNNeo and ACHN-Pin1 cells rescued with ectopic Pin1 expression were assayed for tumorigenicity in a xenograft model
ACHN-Pin1 tumors were histologically similar to ACHN-Neo control tumors, which exhibited necrotic cores surrounded by proliferating cells (Figure 3C)
Summary
Pin is a conserved peptidyl-prolyl isomerase that recognizes phosphorylated serine/threonine-proline motifs (pS/T-P) (Yaffe et al, 1997). The loss of Pin in multiple cell types, such as Pin1À/À primordial germ cells and mouse embryonic fibroblasts (MEF), leads to prolongation of G0-G1-S progression (Atchison et al, 2003; Fujimori et al, 1999; You et al, 2002). Such a delay could be explained by Pin1’s ability to promote the expression and stabilization of cyclin D1, underscoring the potential importance of Pin in cancer
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