| Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice. | |
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MedLine Citation:
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PMID: 23143302 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-11-12 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 122 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-12-03 Completed Date: 2013-02-04 Revised Date: 2013-02-20 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 4505-18 Citation Subset: AIM; IM |
Affiliation:
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Division of Cancer Genetics, Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Abnormalities, Multiple
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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:
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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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