title: The prolyl isomerase pin1 regulates mRNA levels of genes with short half-lives by targeting specific RNA binding proteins.
abstract: 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.
authors.affiliation: Hauptman-Woodward Medical Research Institute, SUNY at Buffalo, New York, United States of America.
authors.forename: Nithya
authors.initials: N
authors.lastname: Krishnan
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Titus
authors.affiliation: Hauptman-Woodward Medical Research Institute, SUNY at Buffalo, New York, United States of America ; Department of Structural Biology, SUNY at Buffalo, New York, United States of America ; Department of Biochemistry and Cell Biology, Rice University, Houston, Texas, United States of America.
authors.forename: Roopa
authors.initials: R
authors.lastname: Thapar
mesh_terms: D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D004261:DNA Replication; D051959:ELAV Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D015894:Genome, Human; D057809:HEK293 Cells; D006207:Half-Life; D006367:HeLa Cells; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D020411:Oligonucleotide Array Sequence Analysis; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051959:ELAV Proteins; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D006657:Histones; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010716:Phosphatidylinositols; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase