Unregulated smooth-muscle myosin in human intestinal neoplasia.

@article{citeulike:2648751, 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.}, address = {Department of Medical Genetics and Division of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and Genome Scale Biology Program, Biomedicum Helsinki, University of Helsinki, 00014, Helsinki, Finland.}, author = {Alhopuro, P. and Phichith, D. and Tuupanen, S. and Sammalkorpi, H. and Nybondas, M. and Saharinen, J. and Robinson, J. P. and Yang, Z. and Chen, L. Q. and Orntoft, T. and Mecklin, J. P. and J\"{a}rvinen, H. and Eng, C. and Moeslein, G. and Shibata, D. and Houlston, R. S. and Lucassen, A. and Tomlinson, I. P. and Launonen, V. and Ristim\"{a}ki, A. and Arango, D. and Karhu, A. and Sweeney, H. L. and Aaltonen, L. A. }, citeulike-article-id = {2648751}, doi = {http://dx.doi.org/10.1073/pnas.0801213105}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, month = {April}, number = {14}, pages = {5513--5518}, posted-at = {2008-04-10 10:33:16}, priority = {2}, title = {Unregulated smooth-muscle myosin in human intestinal neoplasia.}, url = {http://dx.doi.org/10.1073/pnas.0801213105}, volume = {105}, year = {2008} }

TY - JOUR ID - citeulike:2648751 L3 - citeulike-article-id:2648751 N2 - 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. IS - 14 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 1091-6490 AD - Department of Medical Genetics and Division of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and Genome Scale Biology Program, Biomedicum Helsinki, University of Helsinki, 00014, Helsinki, Finland. EP - 5518 TI - Unregulated smooth-muscle myosin in human intestinal neoplasia. VL - 105 SP - 5513 AU - Alhopuro, P AU - Phichith, D AU - Tuupanen, S AU - Sammalkorpi, H AU - Nybondas, M AU - Saharinen, J AU - Robinson, JP AU - Yang, Z AU - Chen, LQ AU - Orntoft, T AU - Mecklin, JP AU - Järvinen, H AU - Eng, C AU - Moeslein, G AU - Shibata, D AU - Houlston, RS AU - Lucassen, A AU - Tomlinson, IP AU - Launonen, V AU - Ristimäki, A AU - Arango, D AU - Karhu, A AU - Sweeney, HL AU - Aaltonen, LA PY - 2008/04/08/ UR - http://dx.doi.org/10.1073/pnas.0801213105 ER -