title: Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice.
abstract: 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.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Nishio
authors.forename: Koichi
authors.initials: K
authors.lastname: Hamada
authors.forename: Kohichi
authors.initials: K
authors.lastname: Kawahara
authors.forename: Masato
authors.initials: M
authors.lastname: Sasaki
authors.forename: Fumihito
authors.initials: F
authors.lastname: Noguchi
authors.forename: Shuhei
authors.initials: S
authors.lastname: Chiba
authors.forename: Kensaku
authors.initials: K
authors.lastname: Mizuno
authors.forename: Satoshi O
authors.initials: SO
authors.lastname: Suzuki
authors.forename: Youyi
authors.initials: Y
authors.lastname: Dong
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tokuda
authors.forename: Takumi
authors.initials: T
authors.lastname: Morikawa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hikasa
authors.forename: Jonathan
authors.initials: J
authors.lastname: Eggenschwiler
authors.forename: Norikazu
authors.initials: N
authors.lastname: Yabuta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nojima
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishina
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Toru
authors.initials: T
authors.lastname: Nakano
authors.forename: Satoshi
authors.initials: S
authors.lastname: Itami
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D046149:Embryo Culture Techniques; D004622:Embryo, Mammalian / Q000473:pathology; D005260:Female; D005804:Genes, Lethal; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006706:Homeostasis; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012868:Skin Abnormalities / Q000235:genetics / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C432417:MOB1 protein, mouse; C529494:Mob1b protein, mouse; D010750:Phosphoproteins; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C490501:Lats1 protein, mouse; C522633:LATS2 protein, mouse; D017346:Protein Serine-Threonine Kinases