Journal
ONCOTARGET
Volume 9, Issue 1, Pages 21-36Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.22940
Keywords
senescence; SASP; osteopontin; c-Myb; C/EBP beta
Categories
Funding
- NIH [5 R01 CA130919, F31 CA189669, P50 CA094056]
- NIH Cellular Biochemical and Molecular Sciences Pre-doctoral Training Grant [T32 GM007067]
- American Cancer Society Research Scholar Award
- Alvin J. Siteman Cancer Center Siteman Investment Program (Foundation for Barnes-Jewish Hospital's Cancer Frontier Fund)
- Alvin J. Siteman Cancer Center Siteman Investment Program (Fashion Footwear Charitable Foundation of New York, Inc.)
- Alvin J. Siteman Cancer Center Siteman Investment Program (Barnard Trust)
- Alvin J. Siteman Cancer Center Siteman Investment Program (National Cancer Institute Cancer Center Support Grant) [P30CA091842]
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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/EBP alpha. In response to senescence, the full-length activating C/EBP beta isoform LAP2 increases binding to the OPN, IL-6, and IL-8 promoters. The importance of both c-Myb and C/EBP beta 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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