title: Integration of proteomic and transcriptomic profiles identifies a novel PDGF-MYC network in human smooth muscle cells.
abstract: BACKGROUND
  Platelet-derived growth factor-BB (PDGF-BB) has been implicated in the proliferation, migration and synthetic activities of smooth muscle cells that characterize physiologic and pathologic tissue remodeling in hollow organs. However, neither the molecular basis of PDGFR-regulated signaling webs, nor the extent to which specific components within these networks could be exploited for therapeutic benefit has been fully elucidated.
  
  
  RESULTS
  Expression profiling and quantitative proteomics analysis of PDGF-treated primary human bladder smooth muscle cells identified 1,695 genes and 241 proteins as differentially expressed versus non-treated cells. Analysis of gene expression data revealed MYC, JUN, EGR1, MYB, RUNX1, as the transcription factors most significantly networked with up-regulated genes. Forty targets were significantly altered at both the mRNA and protein levels. Proliferation, migration and angiogenesis were the biological processes most significantly associated with this signature, and MYC was the most highly networked master regulator. Alterations in master regulators and gene targets were validated in PDGF-stimulated smooth muscle cells in vitro and in a model of bladder injury in vivo. Pharmacologic inhibition of MYC and JUN confirmed their role in SMC proliferation and migration. Network analysis identified the diaphanous-related formin 3 as a novel PDGF target regulated by MYC and JUN, which was necessary for PDGF-stimulated lamellipodium formation.
  
  
  CONCLUSIONS
  These findings provide the first systems-level analysis of the PDGF-regulated transcriptome and proteome in normal smooth muscle cells. The analyses revealed an extensive cohort of PDGF-dependent biological processes and connected key transcriptional effectors to their regulation, significantly expanding current knowledge of PDGF-stimulated signaling cascades. These observations also implicate MYC as a novel target for pharmacological intervention in fibroproliferative expansion of smooth muscle, and potentially in cancers in which PDGFR-dependent signaling or MYC activation promote tumor progression.
authors: Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. Wei.Yang@cshs.org.|Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. Wei.Yang@cshs.org.
authors: Wei
authors: W
authors: Yang
authors: Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, 02115, USA. Aruna_Ramachandran@DFCI.HARVARD.EDU.|Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA. Aruna_Ramachandran@DFCI.HARVARD.EDU.
authors: Aruna
authors: A
authors: Ramachandran
authors: Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. Sungyong.You@cshs.org.
authors: Sungyong
authors: S
authors: You
authors: School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Republic of Korea. jeongdo801@postech.ac.kr.
authors: HyoBin
authors: H
authors: Jeong
authors: Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, 02115, USA. Samantha.Morley@childrens.harvard.edu.|Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA. Samantha.Morley@childrens.harvard.edu.
authors: Samantha
authors: S
authors: Morley
authors: Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, 02115, USA. Michelle.Mulone@childrens.harvard.edu.
authors: Michelle D
authors: MD
authors: Mulone
authors: Clinical Research Center, Boston Children's Hospital, Boston, MA, 02115, USA. Tanya.Logvinenko@childrens.harvard.edu.
authors: Tanya
authors: T
authors: Logvinenko
authors: Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. Jayoung.Kim@cshs.org.|Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. Jayoung.Kim@cshs.org.|Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, 02115, USA. Jayoung.Kim@cshs.org.|Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA. Jayoung.Kim@cshs.org.
authors: Jayoung
authors: J
authors: Kim
authors: School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Republic of Korea. dhhwang@postech.ac.kr.|Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, DGIST, Daegu, 711-873, Republic of Korea. dhhwang@postech.ac.kr.
authors: Daehee
authors: D
authors: Hwang
authors: Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. Michael.Freeman@cshs.org.|Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. Michael.Freeman@cshs.org.|Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, 02115, USA. Michael.Freeman@cshs.org.|Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA. Michael.Freeman@cshs.org.
authors: Michael R
authors: MR
authors: Freeman
authors: Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, 02115, USA. rosalyn.adam@childrens.harvard.edu.|Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA. rosalyn.adam@childrens.harvard.edu.|Urological Diseases Research Center, John F. Enders Research Laboratories, Boston Children's Hospital, Rm 1061.1, Boston, 300 Longwood Avenue, Boston, MA, 02115, USA. rosalyn.adam@childrens.harvard.edu.
authors: Rosalyn M
authors: RM
authors: Adam
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000080865:Formins; D020869:Gene Expression Profiling; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D060066:Protein Interaction Maps; D040901:Proteomics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D001743:Urinary Bladder / Q000166:cytology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C484571:DIAPH3 protein, human; D000080865:Formins; D010982:Platelet-Derived Growth Factor; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D018808:Transcription Factor AP-1