Unregulated smooth-muscle myosin in human intestinal neoplasia

Pia Alhopuro, Denis Phichith, Sari Tuupanen, Heli Sammalkorpi, Miranda Nybondas, Juha Saharinen, James P. Robinson, Zhaohui Yang, Li Qiong Chen, Torben Orntoft, Jukka Pekka Mecklin, Heikki Järvinen, Charis Eng, Gabriela Moeslein, Darryl Shibata, Richard S. Houlston, Anneke Lucassen, Ian P.M. Tomlinson, Virpi Launonen, Ari RistimäkiDiego Arango, Auli Karhu, H. Lee Sweeney, Lauri A. Aaltonen

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

A recent study described a recessive ATPase activating germ-line mutation in smooth-muscle myosin (smmhc/myh11) underlying the zebrafish meltdown (mlt) phenotype. The mlt zebrafish develops intestinal abnormalities reminiscent of human Peutz-Jeghers syndrome (PJS) and juvenile polyposis (JP). To examine the role of MYH11 in human intestinal neoplasia, we searched for MYH11 mutations in patients with colorectal cancer (CRC), PJS and JP. We found somatic protein-elongating frameshift mutations in 55% of CRCs displaying microsatellite instability and in the germ-line of one individual with PJS. Additionally, two somatic missense mutations were found in one microsatellite stable CRC. These two missense mutations, R501L and K1044N, and the frameshift mutations were functionally evaluated. All mutations resulted in unregulated molecules displaying constitutive motor activity, similar to the mutant myosin underlying mlt. Thus, MYH11 mutations appear to contribute also to human intestinal neoplasia. Unregulated MYH11 may affect the cellular energy balance or disturb cell lineage decisions in tumor progenitor cells. These data challenge our view on MYH11 as a passive differentiation marker functioning in muscle contraction and add to our understanding of intestinal neoplasia.

Original languageEnglish (US)
Pages (from-to)5513-5518
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number14
DOIs
StatePublished - Apr 8 2008

Keywords

  • Colorectal cancer
  • Microsatellite instability
  • Peutz-Jeghers syndrome
  • smmhc/myh11

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