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The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program
Roeland F. de Wilde2,
Anirban Maitra2,, and
1 Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
Although a developmental role for Hippo signaling in organ sizecontrol is well appreciated, how this pathway functions in tissueregeneration is largely unknown. Here we address this issueusing a dextran sodium sulfate (DSS)-induced colonic regenerationmodel. We find that regenerating crypts express elevated Yes-associatedprotein (YAP) levels. Inactivation of YAP causes no obviousintestinal defects under normal homeostasis, but severely impairsDSS-induced intestinal regeneration. Conversely, hyperactivationof YAP results in widespread early-onset polyp formation followingDSS treatment. Thus, the YAP oncoprotein must be exquisitelycontrolled in tissue regeneration to allow compensatory proliferationand prevent the intrinsic oncogenic potential of a tissue regenerationprogram.
Key Words: Hippo signaling cancer growth control mouse regeneration
Received for publication August 5, 2010.
Accepted for publication September 14, 2010.