Activation of Stat3 transcription factor by Herpesvirus saimiri STP-A oncoprotein.
The saimiri transforming protein (STP) oncogene of Herpesvirus saimiri subgroup A strain 11 (STP-A11) is not required for viral replication but is required for lymphoid cell immortalization in culture and lymphoma induction in primates. We previously showed that STP-A11 interacts with cellular Src kinase through its SH2 binding motif and that this interaction elicits Src signal transduction. Here we demonstrate that STP-A11 interacts with signal transducer and activator of transcription 3 (Stat3) independently of Src association and that the amino-terminal short proline-rich motif of STP-A11 and the central linker region of Stat3 are necessary for their interaction. STP-A11 formed a triple complex with Src kinase and Stat3 where Src kinase phosphorylated Stat3, resulting in the nuclear localization and transcriptional activation of Stat3. Consequently, the constitutively active Stat3 induced by STP-A11 elicited cellular signal transduction, which ultimately induced cell survival and proliferation upon serum deprivation. Furthermore, this activity was strongly correlated with the induction of Fos, cyclin D1, and Bcl-XL expression. These results demonstrate that STP-A11 independently targets two important cellular signaling molecules, Src and Stat3, and that these proteins cooperate efficiently to induce STP-A11-mediated transformation.
Chung
Young-Hwa
YH
Department of Microbiology and Molecular Genetics, Tumor Virology Division, New England Primate Research Center, Harvard Medical School, 1 Pine Hill Drive, Southborough, MA 01772-9102, USA.
Cho
Nam-hyuk
NH
Garcia
Maria Ines
MI
Lee
Sun-Hwa
SH
Feng
Pinghui
P
Jung
Jae U
JU
D000818:Animals; D019556:COS Cells; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D002472:Cell Transformation, Viral; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006567:Herpesvirus 2, Saimiriine / Q000502:physiology; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D010770:Phosphotransferases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D019061:src-Family Kinases
D004268:DNA-Binding Proteins; D009856:Oncogene Proteins, Viral; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C064364:STP protein, Herpesvirus saimiri; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D010770:Phosphotransferases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human