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CBP/p300 antagonises EGFR‐Ras‐Erk signalling and suppresses increased Ras‐Erk signalling‐induced tumour formation in mice
Author(s) -
Ichise Taeko,
Yoshida Nobuaki,
Ichise Hirotake
Publication year - 2019
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5279
Subject(s) - mapk/erk pathway , cancer research , keratinocyte , anti apoptotic ras signalling cascade , biology , cell growth , proto oncogene proteins c myc , creb binding protein , epidermal growth factor receptor , hedgehog signaling pathway , downregulation and upregulation , microbiology and biotechnology , transcription factor , signal transduction , creb , cell culture , cancer , genetics , gene
CREB‐binding protein (CBP) and p300 have oncogenic properties; both co‐operate with pro‐oncogenic transcription factors downstream of Ras‐Erk signalling to support cell proliferation. By contrast, missense, truncating and in‐frame mutations of CBP/p300 are found frequently in some human cancers, including cutaneous squamous cell carcinomas that originate from epidermal keratinocytes. Data support that dysfunction of CBP/p300 contributes to keratinocyte hyperproliferation and tumourigenesis; however, the mechanism by which dysfunction of CBP/p300 affects keratinocytes is unknown. Here, we used mice harbouring keratinocyte‐specific genetic modifications to examine the role of CBP/p300 in the epidermis. While a single copy of either Crebbp or Ep300 was necessary and sufficient for maintaining epidermal development, reduced expression of CBP/p300 strengthened the Ras‐Erk signalling‐induced hyperplastic phenotype of epidermal keratinocytes. Reduced CBP/p300 expression increased ligand‐induced EGFR activity while decreasing basal expression of Mig6, a negative regulator of EGFR. A reduction in CBP/p300, in combination with increased Ras‐Erk signalling, also promoted epidermal tumour formation in mice. Thus, our findings support that CBP/p300 acts as a tumour suppressor in epidermal keratinocytes by counteracting EGFR‐Ras‐Erk signalling. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.