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PLoS Genet. 2018 Sep 6;14(9):e1007611. doi: 10.1371/journal.pgen.1007611. eCollection 2018 Sep.

The conserved protective cyclic AMP-phosphodiesterase function PDE4B is expressed in the adenoma and adjacent normal colonic epithelium of mammals and silenced in colorectal cancer.

Author information

1
McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
2
Laboratory of Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
3
Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
4
Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
5
Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
6
Division of Hematology and Medical Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
7
Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

Abstract

Conservation over three mammalian genera-the mouse, rat, and human-has been found for a subset of the transcripts whose level differs between the adenoma and normal epithelium of the colon. Pde4b is one of the triply conserved transcripts whose level is enhanced both in the colonic adenoma and in the normal colonic epithelium, especially adjacent to adenomas. It encodes the phosphodiesterase PDE4B, specific for cAMP. Loss of PDE4B function in the ApcMin/+ mouse leads to a significant increase in the number of colonic adenomas. Similarly, Pde4b-deficient ApcMin/+ mice are hypersensitive to treatment by the inflammatory agent DSS, becoming moribund soon after treatment. These observations imply that the PDE4B function protects against ApcMin-induced adenomagenesis and inflammatory lethality. The paradoxical enhancement of the Pde4b transcript in the adenoma versus this inferred protective function of PDE4B can be rationalized by a feedback model in which PDE4B is first activated by early oncogenic stress involving cAMP and then, as reported for frank human colon cancer, inactivated by epigenetic silencing.

PMID:
30188895
PMCID:
PMC6143270
DOI:
10.1371/journal.pgen.1007611
[Indexed for MEDLINE]
Free PMC Article

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