Peptidyl-prolyl isomerase Pin1 markedly enhances the oncogenic activity of the rel proteins in the nuclear factor-kappaB family.

The peptidyl-prolyl isomerase Pin1 is frequently up-regulated in human cancers in which Rel/nuclear factor-kappaB (NF-kappaB) is constitutively activated, but its role in these cancers remains to be determined, and evidence is still lacking to show that Pin1 contributes to cell transformation by Rel/NF-kappaB. Rel/NF-kappaB transcriptional and oncogenic activities are modulated by several posttranslational modifications and coregulatory proteins, and previous studies showed that cytokine treatment induces binding of Pin1 to the RelA subunit of NF-kappaB, thereby enhancing RelA nuclear localization and stability. Here we show that Pin1 associates with the Rel subunits of NF-kappaB that are implicated in leukemia/lymphomagenesis and modulates their transcriptional and oncogenic activities. Pin1 markedly enhanced transformation of primary lymphocytes by the human c-Rel protein and also increased cell transformation by the potent viral Rel/NF-kappaB oncoprotein v-Rel, in contrast to a Pin1 mutant in the WW domain involved in interaction with NF-kappaB. Pin1 promoted nuclear accumulation of Rel proteins in the absence of activating stimuli. Importantly, inhibition of Pin1 function with the pharmacologic inhibitor juglone or with Pin1-specific shRNA led to cytoplasmic relocalization of endogenous c-Rel in human lymphoma-derived cell lines, markedly interfered with lymphoma cell proliferation, and suppressed endogenous Rel/NF-kappaB-dependent gene expression. Together, these results show that Pin1 is an important regulator of Rel/NF-kappaB transforming activity and suggest that Pin1 may be a potential therapeutic target in Rel/NF-kappaB-dependent leukemia/lymphomas.

[1]  P. van der Sluijs,et al.  Juglone Inactivates Cysteine-rich Proteins Required for Progression through Mitosis* , 2008, Journal of Biological Chemistry.

[2]  K. Lu,et al.  Phosphorylation-specific prolyl isomerase Pin1 as a new diagnostic and therapeutic target for cancer. , 2008, Current cancer drug targets.

[3]  Anirvan M. Sengupta,et al.  Repression of B-cell linker (BLNK) and B-cell adaptor for phosphoinositide 3-kinase (BCAP) is important for lymphocyte transformation by rel proteins. , 2008, Cancer research.

[4]  Xiao Zhen Zhou,et al.  The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease , 2007, Nature Reviews Molecular Cell Biology.

[5]  Ross Tubo,et al.  Mesenchymal stem cells within tumour stroma promote breast cancer metastasis , 2007, Nature.

[6]  Vyomesh Patel,et al.  Inhibition of Pin1 reduces glutamate-induced perikaryal accumulation of phosphorylated neurofilament-H in neurons. , 2007, Molecular biology of the cell.

[7]  Elisabeth S Yeh,et al.  PIN1, the cell cycle and cancer , 2007, Nature Reviews Cancer.

[8]  R. Siebert,et al.  Gains of REL in primary mediastinal B‐cell lymphoma coincide with nuclear accumulation of REL protein , 2007, Genes, chromosomes & cancer.

[9]  R. Braun,et al.  Pin1 Modulates the Type 1 Immune Response , 2007, PloS one.

[10]  David R Williams,et al.  Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis. , 2006, Blood.

[11]  C Gélinas,et al.  Current insights into the regulation of programmed cell death by NF-κB , 2006, Oncogene.

[12]  Y. Kwong,et al.  PIN1 expression contributes to hepatic carcinogenesis , 2006, The Journal of pathology.

[13]  L. Espinosa,et al.  Efficient nuclear export of p65-IκBα complexes requires 14-3-3 proteins , 2006, Journal of Cell Science.

[14]  L. Buée,et al.  The Peptidylprolyl cis/trans-Isomerase Pin1 Modulates Stress-induced Dephosphorylation of Tau in Neurons , 2006, Journal of Biological Chemistry.

[15]  M. J. You,et al.  The suppression of SH3BGRL is important for v-Rel-mediated transformation , 2006, Oncogene.

[16]  Shridar Ganesan,et al.  X chromosomal abnormalities in basal-like human breast cancer. , 2006, Cancer cell.

[17]  Elisabeth S Yeh,et al.  The Loss of PIN1 Deregulates Cyclin E and Sensitizes Mouse Embryo Fibroblasts to Genomic Instability* , 2006, Journal of Biological Chemistry.

[18]  Michael Karin,et al.  IKK/NF-κB signaling: balancing life and death – a new approach to cancer therapy , 2005 .

[19]  T. Golub,et al.  NFkappaB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes. , 2005, Blood.

[20]  Adam A. Margolin,et al.  Reverse engineering of regulatory networks in human B cells , 2005, Nature Genetics.

[21]  R. Abseher,et al.  Microarray gene expression profiling of B-cell chronic lymphocytic leukemia subgroups defined by genomic aberrations and VH mutation status. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  Priti Garg,et al.  Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis , 2004, The EMBO journal.

[23]  M. Karin,et al.  The two NF-κB activation pathways and their role in innate and adaptive immunity , 2004 .

[24]  S. Fan,et al.  PIN1 overexpression and β-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma , 2004, Oncogene.

[25]  Joseph R. Nevins,et al.  A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells , 2004, Nature Cell Biology.

[26]  N. Perkins,et al.  Active Repression of Antiapoptotic Gene Expression by RelA(p65) NF-κB , 2004 .

[27]  B. Rayet,et al.  Divergent C-terminal transactivation domains of Rel/NF-κB proteins are critical determinants of their oncogenic potential in lymphocytes , 2004, Oncogene.

[28]  F. Ajchenbaum‐Cymbalista,et al.  Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway. , 2004, Blood.

[29]  A. Ryo,et al.  Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. , 2003, Molecular cell.

[30]  Xiao Zhen Zhou,et al.  Pin1 modulates the structure and function of human RNA polymerase II. , 2003, Genes & development.

[31]  T. Gilmore,et al.  Deletion of either C-terminal transactivation subdomain enhances the in vitro transforming activity of human transcription factor REL in chicken spleen cells , 2003, Oncogene.

[32]  Anna Frolov,et al.  The prolyl isomerase Pin1 is a novel prognostic marker in human prostate cancer. , 2003, Cancer research.

[33]  D. W. Kim,et al.  Mouse Mammary Tumor Virus c-rel Transgenic Mice Develop Mammary Tumors , 2003, Molecular and Cellular Biology.

[34]  N. Perkins,et al.  p53 Represses Cyclin D1 Transcription through Down Regulation of Bcl-3 and Inducing Increased Association of the p52 NF-κB Subunit with Histone Deacetylase 1 , 2003, Molecular and Cellular Biology.

[35]  L. Pham,et al.  Inhibition of Constitutive NF-κB Activation in Mantle Cell Lymphoma B Cells Leads to Induction of Cell Cycle Arrest and Apoptosis1 , 2003, The Journal of Immunology.

[36]  N. Munshi,et al.  NF-κB as a Therapeutic Target in Multiple Myeloma* , 2002, The Journal of Biological Chemistry.

[37]  J. Noel,et al.  Critical Role of WW Domain Phosphorylation in Regulating Phosphoserine Binding Activity and Pin1 Function* , 2002, The Journal of Biological Chemistry.

[38]  Ulrich Siebenlist,et al.  Constitutive Nuclear Factor κB Activity Is Required for Survival of Activated B Cell–like Diffuse Large B Cell Lymphoma Cells , 2001, The Journal of experimental medicine.

[39]  T. Gilmore,et al.  Malignant transformation of primary chicken spleen cells by human transcription factor c-Rel , 2001, Oncogene.

[40]  Tianhua Niu,et al.  Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c‐Jun towards cyclin D1 , 2001, The EMBO journal.

[41]  B. Dörken,et al.  Constitutive NF-kappaB maintains high expression of a characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells. , 2001, Blood.

[42]  W. Funkhouser,et al.  Selective activation of NF-κB subunits in human breast cancer: potential roles for NF-κB2/p52 and for Bcl-3 , 2000, Oncogene.

[43]  M. Hannink,et al.  Loss of IκBα-Mediated Control over Nuclear Import and DNA Binding Enables Oncogenic Activation of c-Rel , 1998, Molecular and Cellular Biology.

[44]  G. Fischer,et al.  Selective inactivation of parvulin-like peptidyl-prolyl cis/trans isomerases by juglone. , 1998, Biochemistry.

[45]  A. E. Rogers,et al.  Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. , 1997, The Journal of clinical investigation.

[46]  M. Kirschner,et al.  Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. , 1997, Science.

[47]  R. Ranganathan,et al.  Structural and Functional Analysis of the Mitotic Rotamase Pin1 Suggests Substrate Recognition Is Phosphorylation Dependent , 1997, Cell.

[48]  T. Hunter,et al.  A human peptidyl–prolyl isomerase essential for regulation of mitosis , 1996, Nature.

[49]  M. Dyer,et al.  B-cell non-Hodgkin's lymphoma cell line (Karpas 1106) with complex translocation involving 18q21.3 but lacking BCL2 rearrangement and expression. , 1994, Blood.

[50]  W. Olson,et al.  The v-rel oncogene of avian reticuloendotheliosis virus transforms immature and mature lymphoid cells of the B cell lineage in vitro. , 1991, Virology.