The prolyl isomerase pin1 regulates mRNA levels of genes with short half-lives by targeting specific RNA binding proteins

The peptidyl-prolyl isomerase Pin1 is over-expressed in several cancer tissues is a potential prognostic marker in prostate cancer, and Pin1 ablation can suppress tumorigenesis in breast and prostate cancers. Pin1 can co-operate with activated ErbB2 or Ras to enhance tumorigenesis. It does so by reg...

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Bibliographic Details
Published in:PloS one 2014-01, Vol.9 (1), p.e85427-e85427
Main Authors: Krishnan, Nithya, Titus, Mark A, Thapar, Roopa
Format: Article
Language:English
Subjects:
Abundance
Alzheimer's disease
Androgen receptors
Binding proteins
Binding sites
Biochemistry
Biology
Breast cancer
c-Myc protein
Cancer
Cell Adhesion
Cell cycle
Cell growth
Cell Movement
Cell Proliferation
Cells (Biology)
Cyclin D1
Cyclin E
Decay
Deoxyribonucleic acid
Deregulation
DNA
DNA biosynthesis
DNA microarrays
DNA Replication
ELAV Proteins - genetics
ELAV Proteins - metabolism
ErbB-2 protein
Estrogens
Gene expression
Gene Expression Profiling
Gene Expression Regulation
Gene Knockdown Techniques
Genes
Genome, Human
Genomes
Genomics
Granulocyte-macrophage colony-stimulating factor
Half-Life
HEK293 Cells
HeLa Cells
Heterogeneous Nuclear Ribonucleoprotein D0
Heterogeneous-Nuclear Ribonucleoprotein D - genetics
Heterogeneous-Nuclear Ribonucleoprotein D - metabolism
Histones - genetics
Histones - metabolism
Humans
HuR protein
Kinases
Leukocyte migration
Leukocytes
Mammalian cells
Medical research
Messenger RNA
Metabolism
mRNA stability
mRNA turnover
Myc protein
NIMA-Interacting Peptidylprolyl Isomerase
Oligonucleotide Array Sequence Analysis
p53 Protein
Parathyroid hormones
Peptidylprolyl isomerase
Peptidylprolyl Isomerase - antagonists & inhibitors
Peptidylprolyl Isomerase - genetics
Peptidylprolyl Isomerase - metabolism
Phosphatidylinositol
Phosphatidylinositols - metabolism
Phosphorylation
Pin1 protein
Post-transcription
Prognosis
Prostate
Prostate cancer
Protein binding
Proteins
Ribonucleic acid
RNA
RNA Stability
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
RNA-binding protein
Rodents
Sequences
Signal Transduction
Signaling
Statistical analysis
Tissues
Transforming growth factors
Tumor proteins
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Summary:The peptidyl-prolyl isomerase Pin1 is over-expressed in several cancer tissues is a potential prognostic marker in prostate cancer, and Pin1 ablation can suppress tumorigenesis in breast and prostate cancers. Pin1 can co-operate with activated ErbB2 or Ras to enhance tumorigenesis. It does so by regulating the activity of proteins that are essential for gene expression and cell proliferation. Several targets of Pin1 such as c-Myc, the Androgen Receptor, Estrogen Receptor-alpha, Cyclin D1, Cyclin E, p53, RAF kinase and NCOA3 are deregulated in cancer. At the posttranscriptional level, emerging evidence indicates that Pin1 also regulates mRNA decay of histone mRNAs, GM-CSF, Pth, and TGFβ mRNAs by interacting with the histone mRNA specific protein SLBP, and the ARE-binding proteins AUF1 and KSRP, respectively. To understand how Pin1 may affect mRNA abundance on a genome-wide scale in mammalian cells, we used RNAi along with DNA microarrays to identify genes whose abundance is significantly altered in response to a Pin1 knockdown. Functional scoring of differentially expressed genes showed that Pin1 gene targets control cell adhesion, leukocyte migration, the phosphatidylinositol signaling system and DNA replication. Several mRNAs whose abundance was significantly altered by Pin1 knockdown contained AU-rich element (ARE) sequences in their 3' untranslated regions. We identified HuR and AUF1 as Pin1 interacting ARE-binding proteins in vivo. Pin1 was also found to stabilize all core histone mRNAs in this study, thereby validating our results from a previously published study. Statistical analysis suggests that Pin1 may target the decay of essential mRNAs that are inherently unstable and have short to medium half-lives. Thus, this study shows that an important biological role of Pin1 is to regulate mRNA abundance and stability by interacting with specific RNA-binding proteins that may play a role in cancer progression.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0085427