Proteomic analysis reveals a novel mechanism induced by the leukemic oncogene Tel/PDGFRβ in stem cells: Activation of the interferon response pathways
Objective proteomic analysis offers opportunities for hypothesis generation on molecular events associated with pathogenesis in stem cells. Relative quantification mass spectrometry was employed to identify pathways affected by Tel/PDGFRβ, an oncogene associated with myeloproliferative neoplasia (MP...
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| Veröffentlicht in: | Stem cell research 2010-11, Vol.5 (3), p.226-243 |
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| creator | Dobbin, E. Graham, C. Freeburn, R.W. Unwin, R.D. Griffiths, J.R. Pierce, A. Whetton, A.D. Wheadon, H. |
| description | Objective proteomic analysis offers opportunities for hypothesis generation on molecular events associated with pathogenesis in stem cells. Relative quantification mass spectrometry was employed to identify pathways affected by Tel/PDGFRβ, an oncogene associated with myeloproliferative neoplasia (MPN). Its effects on over 1800 proteins were quantified with high confidence. Of those up-regulated by Tel/PDGFRβ several were involved in the interferon gamma (IFNγ) response. To validate these observations we employed embryonic and myeloid stem cells models which revealed Tel/PDGFRβ-induced STAT1 up-regulation and activation was responsible for modulating the interferon response. A STAT1 target highly up-regulated was ICSBP, a transcriptional regulator of myeloid and eosinophilic differentiation. ICSBP interacts with CBP/p300 and Ets transcription factors, to promote transcription of additional genes, including the Egr family, key regulators of myelopoiesis. These interferon responses were recapitulated using IFNγ stimulation of stem cells. Thus Tel/PDGFRβ induces aberrant IFN signaling and downstream targets, which may ultimately impact the hematopoietic transcriptional factor network to bias myelomonocytic differentiation in this MPN. |
| doi_str_mv | 10.1016/j.scr.2010.08.001 |
| format | Article |
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Relative quantification mass spectrometry was employed to identify pathways affected by Tel/PDGFRβ, an oncogene associated with myeloproliferative neoplasia (MPN). Its effects on over 1800 proteins were quantified with high confidence. Of those up-regulated by Tel/PDGFRβ several were involved in the interferon gamma (IFNγ) response. To validate these observations we employed embryonic and myeloid stem cells models which revealed Tel/PDGFRβ-induced STAT1 up-regulation and activation was responsible for modulating the interferon response. A STAT1 target highly up-regulated was ICSBP, a transcriptional regulator of myeloid and eosinophilic differentiation. ICSBP interacts with CBP/p300 and Ets transcription factors, to promote transcription of additional genes, including the Egr family, key regulators of myelopoiesis. These interferon responses were recapitulated using IFNγ stimulation of stem cells. 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Relative quantification mass spectrometry was employed to identify pathways affected by Tel/PDGFRβ, an oncogene associated with myeloproliferative neoplasia (MPN). Its effects on over 1800 proteins were quantified with high confidence. Of those up-regulated by Tel/PDGFRβ several were involved in the interferon gamma (IFNγ) response. To validate these observations we employed embryonic and myeloid stem cells models which revealed Tel/PDGFRβ-induced STAT1 up-regulation and activation was responsible for modulating the interferon response. A STAT1 target highly up-regulated was ICSBP, a transcriptional regulator of myeloid and eosinophilic differentiation. ICSBP interacts with CBP/p300 and Ets transcription factors, to promote transcription of additional genes, including the Egr family, key regulators of myelopoiesis. These interferon responses were recapitulated using IFNγ stimulation of stem cells. Thus Tel/PDGFRβ induces aberrant IFN signaling and downstream targets, which may ultimately impact the hematopoietic transcriptional factor network to bias myelomonocytic differentiation in this MPN.</description><subject>Animals</subject><subject>ETS Translocation Variant 6 Protein</subject><subject>Interferon Regulatory Factors - metabolism</subject><subject>Interferon-gamma - metabolism</subject><subject>Mass Spectrometry</subject><subject>Mice</subject><subject>Myelopoiesis</subject><subject>Proteome - analysis</subject><subject>Proto-Oncogene Proteins c-ets - metabolism</subject><subject>Receptor, Platelet-Derived Growth Factor beta - metabolism</subject><subject>Repressor Proteins - metabolism</subject><subject>Signal Transduction</subject><subject>STAT1 Transcription Factor - metabolism</subject><subject>Stem Cells - metabolism</subject><subject>Up-Regulation</subject><issn>1873-5061</issn><issn>1876-7753</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1uFDEQhS0EIiFwADbIO1Y98X93wyoKJCBFIkJhbbndZcZDtz3Y7kFzEu7BQTgTnkxgyapc1veequoh9JKSFSVUnW9W2aYVI7Un3YoQ-gid0q5VTdtK_vj-zRtJFD1Bz3LeECJ71rGn6ISRrpW9FKfo522KBeLsLTbBTPvsM06wAzNlbHCIO5jwDHZtgs8z9mFcLIx42OOyBjzB8g0O0hhs_AoB8B1M57fvrq8-__5VYZwLzNjCNOU3-MIWvzPFx4Cju5f7UCA5SPUnQd7GkAFvTVn_MPv8HD1xdQZ48VDP0Jer93eXH5qbT9cfLy9uGsslKw2lnPXQd4oDVQMXnA_toEbHiHLEGcOcNK0cqBSD4LaTVpCxF1RYZyUVruNn6PXRd5vi9wVy0bPPh4lNgLhk3cpWKK4oqyQ9kjbFnBM4vU1-NmmvKdGHOPRG1zj0IQ5NOl3jqJpXD-7LMMP4T_H3_hV4ewSg7rjzkKqFh1Bv7BPYosfo_2P_ByrYnfs</recordid><startdate>20101101</startdate><enddate>20101101</enddate><creator>Dobbin, E.</creator><creator>Graham, C.</creator><creator>Freeburn, R.W.</creator><creator>Unwin, R.D.</creator><creator>Griffiths, J.R.</creator><creator>Pierce, A.</creator><creator>Whetton, A.D.</creator><creator>Wheadon, H.</creator><general>Elsevier B.V</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20101101</creationdate><title>Proteomic analysis reveals a novel mechanism induced by the leukemic oncogene Tel/PDGFRβ in stem cells: Activation of the interferon response pathways</title><author>Dobbin, E. ; Graham, C. ; Freeburn, R.W. ; Unwin, R.D. ; Griffiths, J.R. ; Pierce, A. ; Whetton, A.D. ; Wheadon, H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c352t-11329e9863e16b3433b7b6df206f0faa2f5a75b154b43c85c40d9414cfc514f83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>ETS Translocation Variant 6 Protein</topic><topic>Interferon Regulatory Factors - metabolism</topic><topic>Interferon-gamma - metabolism</topic><topic>Mass Spectrometry</topic><topic>Mice</topic><topic>Myelopoiesis</topic><topic>Proteome - analysis</topic><topic>Proto-Oncogene Proteins c-ets - metabolism</topic><topic>Receptor, Platelet-Derived Growth Factor beta - metabolism</topic><topic>Repressor Proteins - metabolism</topic><topic>Signal Transduction</topic><topic>STAT1 Transcription Factor - metabolism</topic><topic>Stem Cells - metabolism</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dobbin, E.</creatorcontrib><creatorcontrib>Graham, C.</creatorcontrib><creatorcontrib>Freeburn, R.W.</creatorcontrib><creatorcontrib>Unwin, R.D.</creatorcontrib><creatorcontrib>Griffiths, J.R.</creatorcontrib><creatorcontrib>Pierce, A.</creatorcontrib><creatorcontrib>Whetton, A.D.</creatorcontrib><creatorcontrib>Wheadon, H.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Stem cell research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dobbin, E.</au><au>Graham, C.</au><au>Freeburn, R.W.</au><au>Unwin, R.D.</au><au>Griffiths, J.R.</au><au>Pierce, A.</au><au>Whetton, A.D.</au><au>Wheadon, H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Proteomic analysis reveals a novel mechanism induced by the leukemic oncogene Tel/PDGFRβ in stem cells: Activation of the interferon response pathways</atitle><jtitle>Stem cell research</jtitle><addtitle>Stem Cell Res</addtitle><date>2010-11-01</date><risdate>2010</risdate><volume>5</volume><issue>3</issue><spage>226</spage><epage>243</epage><pages>226-243</pages><issn>1873-5061</issn><eissn>1876-7753</eissn><abstract>Objective proteomic analysis offers opportunities for hypothesis generation on molecular events associated with pathogenesis in stem cells. Relative quantification mass spectrometry was employed to identify pathways affected by Tel/PDGFRβ, an oncogene associated with myeloproliferative neoplasia (MPN). Its effects on over 1800 proteins were quantified with high confidence. Of those up-regulated by Tel/PDGFRβ several were involved in the interferon gamma (IFNγ) response. To validate these observations we employed embryonic and myeloid stem cells models which revealed Tel/PDGFRβ-induced STAT1 up-regulation and activation was responsible for modulating the interferon response. A STAT1 target highly up-regulated was ICSBP, a transcriptional regulator of myeloid and eosinophilic differentiation. ICSBP interacts with CBP/p300 and Ets transcription factors, to promote transcription of additional genes, including the Egr family, key regulators of myelopoiesis. These interferon responses were recapitulated using IFNγ stimulation of stem cells. 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| subjects | Animals ETS Translocation Variant 6 Protein Interferon Regulatory Factors - metabolism Interferon-gamma - metabolism Mass Spectrometry Mice Myelopoiesis Proteome - analysis Proto-Oncogene Proteins c-ets - metabolism Receptor, Platelet-Derived Growth Factor beta - metabolism Repressor Proteins - metabolism Signal Transduction STAT1 Transcription Factor - metabolism Stem Cells - metabolism Up-Regulation |
| title | Proteomic analysis reveals a novel mechanism induced by the leukemic oncogene Tel/PDGFRβ in stem cells: Activation of the interferon response pathways |
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