title: Activation of cell cycle arrest and apoptosis by the proto-oncogene Pim-2.
abstract: Potent survival effects have been ascribed to the serine/threonine kinase proto-oncogene PIM-2. Elevated levels of PIM-2 are associated with various malignancies. In human cells, a single Pim-2 transcript gives rise mainly to two protein isoforms (34, 41 kDa) that share an identical catalytic site but differ at their N-terminus, due to in-frame alternative translation initiation sites. In this study we observed that the 34 kDa PIM-2 isoform has differential nuclear and cytoplasmic forms in all tested cell lines, suggesting a possible role for the balance between these forms for PIM-2's function. To further study the cellular role of the 34 kDa isoform of PIM-2, an N-terminally HA-tagged form of this isoform was transiently expressed in HeLa cells. Surprisingly, this resulted in increased level of G1 arrested cells, as well as of apoptotic cells. These effects could not be obtained by a Flag-tagged form of the 41 kDa isoform. The G1 arrest and apoptotic effects were associated with an increase in T14/Y15 phosphorylation of CDK2 and proteasom-dependent down-regulation of CDC25A, as well as with up-regulation of p57, E2F-1, and p73. No such effects were obtained upon over-expression of a kinase-dead form of the HA-tagged 34 kDa PIM-2. By either using a dominant negative form of p73, or by over-expressing the 34 kDa PIM-2 in p73-silenced cells, we demonstrated that these effects were p73-dependent. These results demonstrate that while PIM-2 can function as a potent survival factor, it can, under certain circumstances, exhibit pro-apoptotic effects as well.
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Daphna
authors.initials: D
authors.lastname: Levy
authors.forename: Ateret
authors.initials: A
authors.lastname: Davidovich
authors.forename: Shahar
authors.initials: S
authors.lastname: Zirkin
authors.forename: Yulia
authors.initials: Y
authors.lastname: Frug
authors.forename: Amos M
authors.initials: AM
authors.lastname: Cohen
authors.forename: Sara
authors.initials: S
authors.lastname: Shalom
authors.forename: Jeremy
authors.initials: J
authors.lastname: Don
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D045325:HCT116 Cells; D057809:HEK293 Cells; D018922:HL-60 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism
chemical_list: C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C000715470:MAS1 protein, human; D009687:Nuclear Proteins; C490587:PIM2 protein, human; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; D051357:Cyclin-Dependent Kinase 2; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D046988:Proteasome Endopeptidase Complex