Priority Research Papers:

c-Myb and C/EBPβ regulate OPN and other senescence-associated secretory phenotype factors

Kevin C. Flanagan, Elise Alspach, Ermira Pazolli, Shankar Parajuli, Qihao Ren, Laura L. Arthur, Roberto Tapia and Sheila A. Stewart _

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Oncotarget. 2018; 9:21-36. https://doi.org/10.18632/oncotarget.22940

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Kevin C. Flanagan1,2, Elise Alspach1, Ermira Pazolli1, Shankar Parajuli1, Qihao Ren1, Laura L. Arthur1, Roberto Tapia1 and Sheila A. Stewart1,2,3,4

1 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA

2 ICCE Institute, Washington University School of Medicine, St. Louis, MO, USA

3 Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

4 Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA

Correspondence to:

Sheila A. Stewart, email:

Keywords: senescence; SASP; osteopontin; c-Myb; C/EBPβ

Received: July 15, 2017 Accepted: November 09, 2017 Published: December 05, 2017


Tumorigenesis results from the convergence of cell autonomous mutations and corresponding stromal changes that promote tumor cell growth. Senescent cells, which secrete a plethora of pro-tumorigenic factors termed the senescence-associated secretory phenotype (SASP), play an important role in tumor formation. Investigation into SASP regulation revealed that many but not all SASP factors are subject to NF-kB and p38MAPK regulation. However, many pro-tumorigenic SASP factors, including osteopontin (OPN), are not responsive to these canonical pathways leaving the regulation of these factors an open question. We report that the transcription factor c-Myb regulates OPN, IL-6, and IL-8 in addition to 57 other SASP factors. The regulation of OPN is direct as c-Myb binds to the OPN promoter in response to senescence. Further, OPN is also regulated by the known SASP regulator C/EBPβ. In response to senescence, the full-length activating C/EBPβ isoform LAP2 increases binding to the OPN, IL-6, and IL-8 promoters. The importance of both c-Myb and C/EBPβ is underscored by our finding that the depletion of either factor reduces the ability of senescent fibroblasts to promote the growth of preneoplastic epithelial cells.

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PII: 22940