Prolyl isomerase Pin1: a catalyst for oncogenesis and a potential therapeutic target in cancer

Ryo, Akihide; Liou, Yih‐Cherng; Lu, Kun Ping; Wulf, Gerburg M.

doi:10.1242/jcs.00276

Cited by 170 publications

(155 citation statements)

References 140 publications

(228 reference statements)

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“…It has been shown that PIN1 is strikingly overexpressed in breast cancer and that its overexpression leads to the upregulation of cyclin D1 and transformation of breast epithelial cells Ryo et al, 2003). As PIN1 is overexpressed in over half of our studied HCC cases, a critical question is whether overexpression of PIN1 has any effect on the cell transformation of hepatocytes.…”

Section: Introduction Results and Discussionmentioning

confidence: 88%

PIN1 overexpression and β-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma

et al. 2004

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The peptidyl-proplyl-isomerase, PIN1, upregulates b-catenin by inhibiting its interaction with APC. b-catenin accumulation occurs in about 70% of hepatocellular carcinoma (HCC), of which only 20% are due to b-catenin mutations. The role of PIN1 in b-catenin upregulation in HCC was investigated. PIN1 was shown to be overexpressed in more than 50% of HCC. All cases with PIN1 overexpression also showed b-catenin accumulation, with 68% of cases showing concomitant b-catenin and cyclin D1 accumulation. PIN1 was shown to contribute to b-catenin and cyclin D1 overexpression directly by in vitro cell-line transfection experiments. Finally, we showed that PIN1 overexpression and b-catenin gene mutations appeared to be mutually exclusive events, leading to b-catenin accumulation in HCC. These results showed that PIN1 overexpression leading to b-catenin accumulation might be a critical event in hepatocarcinogenesis, and that PIN1 is a potential target for therapeutic intervention in HCC.

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Section: Introduction Results and Discussionmentioning

confidence: 88%

PIN1 overexpression and β-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma

et al. 2004

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“…The prolyl isomerase Pin1 binds to and isomerizes the peptidyl-prolyl bond in specific phosphorylated Ser/Thr-Pro motifs to induce conformational changes in its target proteins (7). These conformational changes can have profound effects on the function of Pin1 substrates, modulating their activity, phosphorylation status, protein-protein interaction, subcellular localization, and stability (16). Interestingly, it was reported that Pin1 regulates SMRT and SRC-3 as downstream effectors of HER-2 signaling (8,17), which is often increased in endocrine-resistant breast tumors and contributes to activate proliferation and/or survival and hormone resistance (6,18).…”

Section: Discussionmentioning

confidence: 99%

The Prolyl Isomerase Pin1 Induces LC-3 Expression and Mediates Tamoxifen Resistance in Breast Cancer

Namgoong

Khanal

Cho

et al. 2010

Journal of Biological Chemistry

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Endocrine therapies, which inhibit estrogen receptor signaling, are the most common and effective treatments for estrogen receptor␣-positive breast cancer. However, the utility of these agents is limited by the frequent development of resistance, and the precise mechanisms underlying endocrine therapy resistance remain incompletely understood. Here, we demonstrate that peptidyl-prolyl isomerase Pin1 is an important determinant of resistance to tamoxifen and show that Pin1 increases E2F-4-and Egr-1-driven expression of LC-3 as a result of an increased interaction with and phosphorylation of MEK1/2. In human tamoxifen-resistant breast cancer, our results show a significant correlation between Pin1 overexpression and high levels of LC-3. Promoter activity as well as expression levels of Pin1 were drastically higher in tamoxifen-resistant MCF7 cells than control MCF7 cells, as were levels of LC-3 mRNA and protein, an autophagy marker. Pin1 Breast cancer is one of the most common malignancies in women and the second most common cause of female cancerrelated deaths (1). However, deaths due to breast cancer have decreased because of the development of targeted therapies, including hormone therapy, in addition to conventional chemotherapy and surgical interventions (1). The majority of breast cancers in postmenopausal women express the estrogen receptors (ERs), 3 and after surgery, they can be treated with hormonal therapy alone, in the absence of more toxic chemotherapy, resulting in a relatively favorable prognosis (2). However, a significant fraction of these hormone-sensitive breast cancer patients will experience disease progression because of resistance to endocrine agents, such as tamoxifen, resulting in mortality (3). Tamoxifen is currently the most widely prescribed, orally active, selective ER modulator for the treatment of breast cancer (4). Although tamoxifen is an ER antagonist in breast tissue, it can also be a partial agonist. Antagonist activity enables the drug to block ER-mediated transcription and cancer cell growth in ER-positive breast cancer cells (5). However, tamoxifen resistance might occur when its agonistic activity overcomes its antagonistic effect (4). This variability could be related, in part, to the cellular milieu of ER co-activators and co-repressors (6). For example, increased levels of co-activators, such as SRC-3, enhance the estrogen agonist properties of tamoxifen, whereas decreased levels of co-repressors, such as SMRT (silencing mediator for retinoid and thyroid receptors) and nuclear receptor corepressor, correlate with acquired tamoxifen resistance (6).Pin1 has two domains: a peptidyl-prolyl cis/trans-isomerase domain at its COOH terminus responsible for isomerization and a WW domain at the NH 2 terminus, which functions as a binding element specific for Ser(P)/Thr-Pro motifs (7). Through these two domains, Pin1 binds to and isomerizes specific Ser(P)/Thr-Pro motifs and catalytically induces conformational changes after phosphorylation (7). Recently, Stanya et al. (8) showed ...

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“…However, recent studies indicate that the deregulation might depend on more complex mechanisms, and other members of the pathway may play complementary roles. Recently, peptidyl-proplylisomerase, PIN1, a member of the pathway, has been shown to be upregulated in breast cancer (Wulf et al, 2001;Ryo et al, 2003) and HCCs (Pang et al, 2004). In Pang et al (2004), it was suggested that PIN1 overexpression and mutation of b-catenin were mutually exclusive events, and they both led to accumulation of b-catenin in HCCs.…”

Section: Discussionmentioning

confidence: 99%

HDPR1, a novel inhibitor of the WNT/β-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing

Yau

Chan

et al. 2004

Oncogene

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Oncogenic activation of the WNT/b-catenin signaling pathway is common in hepatocellular carcinoma (HCC). Dishevelled (Dvl), a key activator of the pathway, inhibits the adenomatous polyposis coli complex, and this leads to the accumulation of b-catenin and promotes tumorigenesis. Recently, a novel inhibitor of Dishevelled, namely Dapper (Dpr), was isolated in Xenopus. To explore whether HDPR1, the human homologue of Dpr, has an anti-oncogenic role in hepatocarcinogenesis, we studied the expression of this gene in HCCs. We found that there were two alternatively spliced transcripts of HDPR1, designated as a and b forms, in human liver. Downregulation of the gene expression was observed in 31 (43%) of the 72 human HCC samples using the primer pair that amplified both transcripts. Furthermore, the HDPR1a was downregulated in 42 (58%) of 72 human HCCs and the downregulation significantly correlated with accumulation of b-catenin. Also, downregulation of HDPR1 by RNA interference in HLE cells led to cytoplasmic accumulation of b-catenin. Furthermore, a CpG island located at the promoter region and exon 1 of the HDPR1 gene was methylated in 22 (51%) of human HCCs. We showed that downregulation of HDPR1, in hepatoma cell lines, was associated with methylation of this CpG island using bisulfite sequencing and 5-aza-2 0 -deoxycytidine demethylation experiment. In addition to methylation-mediated downregulation of HDPR1, allelic loss (13-28% of informative cases) was detected using microsatellite markers flanking the HDPR1 locus. To conclude, downregulation of HDPR1 is common in HCCs, frequently involves hypermethylation of the promoter region, and allelic loss of the HDPR1 locus may also play a role.

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Prolyl isomerase Pin1: a catalyst for oncogenesis and a potential therapeutic target in cancer

Cited by 170 publications

References 140 publications

PIN1 overexpression and β-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma

PIN1 overexpression and β-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma

The Prolyl Isomerase Pin1 Induces LC-3 Expression and Mediates Tamoxifen Resistance in Breast Cancer

HDPR1, a novel inhibitor of the WNT/β-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing

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