Abstract
Phosphorylation on serines or threonines preceding proline (Ser/Thr-Pro) is a major signaling mechanism. The conformation of a subset of phosphorylated Ser/Thr-Pro motifs is regulated by the prolyl isomerase Pin1. Inhibition of Pin1 induces apoptosis and may also contribute to neuronal death in Alzheimer's disease. However, little is known about the role of Pin1 in cancer or in modulating transcription factor activity. Here we report that Pin1 is strikingly overexpressed in human breast cancers, and that its levels correlate with cyclin D1 levels in tumors. Overexpression of Pin1 increases cellular cyclin D1 protein and activates its promoter. Furthermore, Pin1 binds c-Jun that is phosphorylated on Ser63/73-Pro motifs by activated JNK or oncogenic Ras. Moreover, Pin1 cooperates with either activated Ras or JNK to increase transcriptional activity of c-Jun towards the cyclin D1 promoter. Thus, Pin1 is up-regulated in human tumors and cooperates with Ras signaling in increasing c-Jun transcriptional activity towards cyclin D1. Given the crucial roles of Ras signaling and cyclin D1 overexpression in oncogenesis, our results suggest that overexpression of Pin1 may promote tumor growth.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Biomarkers, Tumor / analysis
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Breast / cytology
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Breast / metabolism*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Carcinoma in Situ / genetics
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Carcinoma in Situ / metabolism
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Carcinoma in Situ / pathology
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Cells, Cultured
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Cyclin D1 / genetics*
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Cyclin D1 / metabolism*
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Female
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Gene Expression Regulation / physiology
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Gene Expression Regulation, Neoplastic / physiology*
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Humans
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JNK Mitogen-Activated Protein Kinases
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Middle Aged
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Mitogen-Activated Protein Kinases / metabolism
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NIMA-Interacting Peptidylprolyl Isomerase
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Peptidylprolyl Isomerase / genetics
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Peptidylprolyl Isomerase / metabolism*
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Phosphorylation
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Promoter Regions, Genetic
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Proto-Oncogene Proteins c-jun / metabolism*
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Receptor, ErbB-2 / analysis
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Receptors, Estrogen / analysis
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Signal Transduction / physiology*
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Transcription, Genetic*
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Tumor Cells, Cultured
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ras Proteins / metabolism
Substances
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Biomarkers, Tumor
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NIMA-Interacting Peptidylprolyl Isomerase
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Proto-Oncogene Proteins c-jun
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Receptors, Estrogen
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Cyclin D1
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Receptor, ErbB-2
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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ras Proteins
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PIN1 protein, human
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Peptidylprolyl Isomerase