Document Detail


Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice.
MedLine Citation:
PMID:  23143302     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mps one binder 1a (MOB1A) and MOB1B are key components of the Hippo signaling pathway and are mutated or inactivated in many human cancers. Here we show that intact Mob1a or Mob1b is essential for murine embryogenesis and that loss of the remaining WT Mob1 allele in Mob1a(Δ/Δ)1b(tr/+) or Mob1a(Δ/+)1b(tr/tr) mice results in tumor development. Because most of these cancers resembled trichilemmal carcinomas, we generated double-mutant mice bearing tamoxifen-inducible, keratinocyte-specific homozygous-null mutations of Mob1a and Mob1b (kDKO mice). kDKO mice showed hyperplastic keratinocyte progenitors and defective keratinocyte terminal differentiation and soon died of malnutrition. kDKO keratinocytes exhibited hyperproliferation, apoptotic resistance, impaired contact inhibition, enhanced progenitor self renewal, and increased centrosomes. Examination of Hippo pathway signaling in kDKO keratinocytes revealed that loss of Mob1a/b altered the activities of the downstream Hippo mediators LATS and YAP1. Similarly, YAP1 was activated in some human trichilemmal carcinomas, and some of these also exhibited MOB1A/1B inactivation. Our results clearly demonstrate that MOB1A and MOB1B have overlapping functions in skin homeostasis, and exert their roles as tumor suppressors by regulating downstream elements of the Hippo pathway.
Authors:
Miki Nishio; Koichi Hamada; Kohichi Kawahara; Masato Sasaki; Fumihito Noguchi; Shuhei Chiba; Kensaku Mizuno; Satoshi O Suzuki; Youyi Dong; Masaaki Tokuda; Takumi Morikawa; Hiroki Hikasa; Jonathan Eggenschwiler; Norikazu Yabuta; Hiroshi Nojima; Kentaro Nakagawa; Yutaka Hata; Hiroshi Nishina; Koshi Mimori; Masaki Mori; Takehiko Sasaki; Tak W Mak; Toru Nakano; Satoshi Itami; Akira Suzuki
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-12
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-03     Completed Date:  2013-02-04     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4505-18     Citation Subset:  AIM; IM    
Affiliation:
Division of Cancer Genetics, Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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MeSH Terms
Descriptor/Qualifier:
Abnormalities, Multiple / genetics,  pathology
Animals
Carcinoma / genetics*,  pathology
Cell Differentiation
Cell Transformation, Neoplastic / genetics
Cells, Cultured
Embryo Culture Techniques
Embryo, Mammalian / pathology
Female
Genes, Lethal*
Genetic Association Studies
Genetic Predisposition to Disease
Homeostasis
Homozygote
Humans
Keratinocytes / pathology,  physiology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasms / genetics,  pathology
Phosphoproteins / genetics*,  metabolism
Protein Kinases / genetics*,  metabolism
Protein-Serine-Threonine Kinases / metabolism
Skin / metabolism,  pathology
Skin Abnormalities / genetics,  pathology
Skin Neoplasms / genetics*,  pathology
Tumor Suppressor Proteins / metabolism
Chemical
Reg. No./Substance:
0/MOB1 protein, mouse; 0/Mob1b protein, mouse; 0/Phosphoproteins; 0/Tumor Suppressor Proteins; EC 2.7.-/Protein Kinases; EC 2.7.1.-/Lats1 protein, mouse; EC 2.7.11.1/LATS2 protein, mouse; EC 2.7.11.1/Protein-Serine-Threonine Kinases
Comments/Corrections

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