title: Pin1 regulates the dynamics of c-Myc DNA binding to facilitate target gene regulation and oncogenesis.
abstract: The Myc oncoprotein is considered a master regulator of gene transcription by virtue of its ability to modulate the expression of a large percentage of all genes. However, mechanisms that direct Myc's recruitment to DNA and target gene selection to elicit specific cellular functions have not been well elucidated. Here, we report that the Pin1 prolyl isomerase enhances recruitment of serine 62-phosphorylated Myc and its coactivators to select promoters during gene activation, followed by promoting Myc's release associated with its degradation. This facilitates Myc's activation of genes involved in cell growth and metabolism, resulting in enhanced proproliferative activity, even while controlling Myc levels. In cancer cells with impaired Myc degradation, Pin1 still enhances Myc DNA binding, although it no longer facilitates Myc degradation. Thus, we find that Pin1 and Myc are cooverexpressed in cancer, and this drives a gene expression pattern that we show is enriched in poor-outcome breast cancer subtypes. This study provides new insight into mechanisms regulating Myc DNA binding and oncogenic activity, it reveals a novel role for Pin1 in the regulation of transcription factors, and it elucidates a mechanism that can contribute to oncogenic cooperation between Pin1 and Myc.
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Farrell
authors.forename: Carl
authors.initials: C
authors.lastname: Pelz
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Daniel
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wang
authors.forename: Yulong
authors.initials: Y
authors.lastname: Su
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Janghorban
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Charlie
authors.initials: C
authors.lastname: Morgan
authors.forename: Soren
authors.initials: S
authors.lastname: Impey
authors.forename: Rosalie C
authors.initials: RC
authors.lastname: Sears
mesh_terms: D000818:Animals; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D015533:Transcriptional Activation; D014981:Xenopus; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016271:Proto-Oncogene Proteins c-myc; D029867:Xenopus Proteins; D004247:DNA; D012319:RNA Polymerase II; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; C525404:Pin1 protein, Xenopus