The action of Pdcd4 may be cell type specific: evidence that reduction of dUTPase levels might contribute to its tumor suppressor activity in Bon-1 cells

Pdcd4 (programmed cell death protein 4) was identified as a gene up-regulated during apoptosis and, additionally, seems to have a function as a tumor suppressor. However, there are conflicting data concerning its role in programmed cell death and most results for its action as an inhibitor for neoplastic transformation are derived from experiments with epidermal cells. Therefore, we were interested to investigate if the action of Pdcd4 might be cell type specific. For that purpose we examined the expression of Pdcd4 and several other proteins in various tumor cell lines. We could not find any correlation of Pdcd4 levels and expression of proteins associated with cell cycle and/or apoptosis in different cell lines. Furthermore, we stably transfected two cell lines (Bon-1 and HCT116) to over-express Pdcd4 and analyzed protein expression. Although we found several regulated proteins none of these proteins were affected in both cell lines in the same manner. For instance, dUTPase expression was reduced in Bon-1 cells but not changed in HCT116 cells. This regulation might be important for the sensitivity of cells to anti-cancer drugs like inhibitors of thymidilate synthase. Therefore, we conclude that the function of Pdcd4 might be cell type specific. A role for Pdcd4 in apoptosis or as a tumor suppressor might be limited to certain cell types.

[1]  E. Kremmer,et al.  dUTPase in human neoplastic cells as a potential target for therapeutic intervention. , 2001, Current protein & peptide science.

[2]  H. Kizaki,et al.  Cloning of the TIS gene suppressed by topoisomerase inhibitors. , 1998, Gene.

[3]  Jennifer L. Knies,et al.  Pdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation , 2003, Oncogene.

[4]  Birgit Samans,et al.  Programmed cell death protein 4 suppresses CDK1/cdc2 via induction of p21Waf1/Cip1 , 2004 .

[5]  N. Sonenberg,et al.  The Transformation Suppressor Pdcd4 Is a Novel Eukaryotic Translation Initiation Factor 4A Binding Protein That Inhibits Translation , 2003, Molecular and Cellular Biology.

[6]  E. Kremmer,et al.  Expression of deoxyuridine triphosphatase (dUTPase) in colorectal tumours , 1999, International journal of cancer.

[7]  C. Fujiyama,et al.  Novel human PDCD4 (H731) gene expressed in proliferative cells is expressed in the small duct epithelial cells of the breast as revealed by an anti‐H731 antibody , 1999, Pathology international.

[8]  D. N. Perkins,et al.  Probability‐based protein identification by searching sequence databases using mass spectrometry data , 1999, Electrophoresis.

[9]  H. Mo,et al.  Studies of the Isoprenoid-Mediated Inhibition of Mevalonate Synthesis Applied to Cancer Chemotherapy and Chemoprevention , 2004, Experimental biology and medicine.

[10]  T. Lawrence,et al.  Resistance to fluorodeoxyuridine-induced DNA damage and cytotoxicity correlates with an elevation of deoxyuridine triphosphatase activity and failure to accumulate deoxyuridine triphosphate. , 1993, Cancer research.

[11]  R. Ladner,et al.  Small interfering RNA-mediated suppression of dUTPase sensitizes cancer cell lines to thymidylate synthase inhibition. , 2004, Molecular pharmacology.

[12]  K. Ohyashiki,et al.  Transcriptional profiling of Epstein–Barr virus (EBV) genes and host cellular genes in nasal NK/T-cell lymphoma and chronic active EBV infection , 2006, British Journal of Cancer.

[13]  N. Colburn,et al.  Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis. , 2005, Cancer research.

[14]  R. Arnold,et al.  Programmed Cell Death Protein 4 (PDCD4) Acts As a Tumor Suppressor in Neuroendocrine Tumor Cells , 2004, Annals of the New York Academy of Sciences.

[15]  S. Carr,et al.  Identification of a Consensus Cyclin-dependent Kinase Phosphorylation Site Unique to the Nuclear Form of Human Deoxyuridine Triphosphate Nucleotidohydrolase (*) , 1996, The Journal of Biological Chemistry.

[16]  N. Colburn,et al.  Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  N. Colburn,et al.  A novel transformation suppressor, Pdcd4, inhibits AP-1 transactivation but not NF-κB or ODC transactivation , 2001, Oncogene.

[18]  W. Park,et al.  Up-regulation of PDCD4 in senescent human diploid fibroblasts. , 2002, Biochemical and biophysical research communications.

[19]  N. Colburn,et al.  Tumorigenesis Suppressor Pdcd4 Down-Regulates Mitogen-Activated Protein Kinase Kinase Kinase Kinase 1 Expression To Suppress Colon Carcinoma Cell Invasion , 2006, Molecular and Cellular Biology.

[20]  H. Samuels,et al.  Induction of PDCD4 tumor suppressor gene expression by RAR agonists, antiestrogen and HER-2/neu antagonist in breast cancer cells. Evidence for a role in apoptosis , 2004, Oncogene.

[21]  A. Hasilik,et al.  Pdcd4 inhibits growth of tumor cells by suppression of carbonic anhydrase type II , 2004, Molecular and Cellular Endocrinology.

[22]  B. Samans,et al.  Programmed cell death protein 4 suppresses CDK1/cdc2 via induction of p21(Waf1/Cip1). , 2004, American journal of physiology. Cell physiology.

[23]  H. Kizaki,et al.  Molecular cloning of the genes suppressed in RVC lymphoma cells by topoisomerase inhibitors. , 1996, Biochemical and biophysical research communications.

[24]  Isolation of a novel mouse gene MA-3 that is induced upon programmed cell death , 1996 .

[25]  A. Palmieri,et al.  Potential Markers of Tongue Tumor Progression Selected by cDNA Micro Array , 2005, International journal of immunopathology and pharmacology.

[26]  K. Klempnauer,et al.  Targeted disruption of c-myb in the chicken pre B-cell line DT40 , 2002, Oncogene.

[27]  L. Azzoni,et al.  Differential transcriptional regulation of CD161 and a novel gene, 197/15a, by IL-2, IL-15, and IL-12 in NK and T cells. , 1998, Journal of immunology.

[28]  K. Klempnauer,et al.  The transformation suppressor protein Pdcd4 shuttles between nucleus and cytoplasm and binds RNA , 2003, Oncogene.

[29]  N. Colburn,et al.  Characterization of programmed cell death 4 in multiple human cancers reveals a novel enhancer of drug sensitivity. , 2004, Molecular cancer therapeutics.

[30]  A. Hartl,et al.  Particulate nitrocellulose as a solid phase for protein immobilization in immuno-affinity chromatography. , 1993, Journal of immunological methods.

[31]  T. Honjo,et al.  Isolation of a novel mouse gene MA-3 that is induced upon programmed cell death. , 1995, Gene.

[32]  H. Zhang,et al.  Involvement of programmed cell death 4 in transforming growth factor-β1-induced apoptosis in human hepatocellular carcinoma , 2006, Oncogene.

[33]  K. Klempnauer,et al.  The chicken Pdcd4 gene is regulated by v-Myb , 2001, Oncogene.

[34]  R. Carmody,et al.  DUG is a novel homologue of translation initiation factor 4G that binds eIF4A. , 2002, Biochemical and biophysical research communications.

[35]  Iver Petersen,et al.  Loss of PDCD4 expression in human lung cancer correlates with tumour progression and prognosis , 2003, The Journal of pathology.