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 F Ørntoft, 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 journalArticleScientificpeer-review

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
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number14
Pages (from-to)5513-5518
Number of pages6
ISSN0027-8424
DOIs
Publication statusPublished - 2008
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 311 Basic medicine

Cite this

Alhopuro, Pia ; Phichith, Denis ; Tuupanen, Sari ; Sammalkorpi, Heli ; Nybondas, Miranda ; Saharinen, Juha ; Robinson, James P ; Yang, Zhaohui ; Chen, Li-Qiong ; Ørntoft, Torben F ; Mecklin, Jukka-Pekka ; Järvinen, Heikki ; Eng, Charis ; Moeslein, Gabriela ; Shibata, Darryl ; Houlston, Richard S ; Lucassen, Anneke ; Tomlinson, Ian P. M ; Launonen, Virpi ; Ristimäki, Ari ; Arango, Diego ; Karhu, Auli ; Sweeney, H. Lee ; Aaltonen, Lauri A. / Unregulated smooth-muscle myosin in human intestinal neoplasia. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 14. pp. 5513-5518.
@article{7dd24ed00fde430ba9c54860ae682560,
title = "Unregulated smooth-muscle myosin in human intestinal neoplasia",
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.",
keywords = "311 Basic medicine",
author = "Pia Alhopuro and Denis Phichith and Sari Tuupanen and Heli Sammalkorpi and Miranda Nybondas and Juha Saharinen and Robinson, {James P} and Zhaohui Yang and Li-Qiong Chen and {\O}rntoft, {Torben F} and Jukka-Pekka Mecklin and Heikki J{\"a}rvinen and Charis Eng and Gabriela Moeslein and Darryl Shibata and Houlston, {Richard S} and Anneke Lucassen and Tomlinson, {Ian P. M} and Virpi Launonen and Ari Ristim{\"a}ki and Diego Arango and Auli Karhu and Sweeney, {H. Lee} and Aaltonen, {Lauri A}",
year = "2008",
doi = "10.1073/pnas.0801213105",
language = "English",
volume = "105",
pages = "5513--5518",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "14",

}

Alhopuro, P, Phichith, D, Tuupanen, S, Sammalkorpi, H, Nybondas, M, Saharinen, J, Robinson, JP, Yang, Z, Chen, L-Q, Ørntoft, TF, Mecklin, J-P, Järvinen, H, Eng, C, Moeslein, G, Shibata, D, Houlston, RS, Lucassen, A, Tomlinson, IPM, Launonen, V, Ristimäki, A, Arango, D, Karhu, A, Sweeney, HL & Aaltonen, LA 2008, 'Unregulated smooth-muscle myosin in human intestinal neoplasia', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 14, pp. 5513-5518. https://doi.org/10.1073/pnas.0801213105

Unregulated smooth-muscle myosin in human intestinal neoplasia. / Alhopuro, Pia; Phichith, Denis; Tuupanen, Sari; Sammalkorpi, Heli; Nybondas, Miranda; Saharinen, Juha; Robinson, James P; Yang, Zhaohui; Chen, Li-Qiong; Ørntoft, Torben F; Mecklin, Jukka-Pekka; Järvinen, Heikki; Eng, Charis; Moeslein, Gabriela; Shibata, Darryl; Houlston, Richard S; Lucassen, Anneke; Tomlinson, Ian P. M; Launonen, Virpi; Ristimäki, Ari; Arango, Diego; Karhu, Auli; Sweeney, H. Lee; Aaltonen, Lauri A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 14, 2008, p. 5513-5518.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Unregulated smooth-muscle myosin in human intestinal neoplasia

AU - Alhopuro, Pia

AU - Phichith, Denis

AU - Tuupanen, Sari

AU - Sammalkorpi, Heli

AU - Nybondas, Miranda

AU - Saharinen, Juha

AU - Robinson, James P

AU - Yang, Zhaohui

AU - Chen, Li-Qiong

AU - Ørntoft, Torben F

AU - Mecklin, Jukka-Pekka

AU - Järvinen, Heikki

AU - Eng, Charis

AU - Moeslein, Gabriela

AU - Shibata, Darryl

AU - Houlston, Richard S

AU - Lucassen, Anneke

AU - Tomlinson, Ian P. M

AU - Launonen, Virpi

AU - Ristimäki, Ari

AU - Arango, Diego

AU - Karhu, Auli

AU - Sweeney, H. Lee

AU - Aaltonen, Lauri A

PY - 2008

Y1 - 2008

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.

AB - 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.

KW - 311 Basic medicine

U2 - 10.1073/pnas.0801213105

DO - 10.1073/pnas.0801213105

M3 - Article

VL - 105

SP - 5513

EP - 5518

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 14

ER -