Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice
Miki Nishio, … , Satoshi Itami, Akira Suzuki
Miki Nishio, … , Satoshi Itami, Akira Suzuki
Published November 12, 2012
Citation Information: J Clin Invest. 2012;122(12):4505-4518. https://doi.org/10.1172/JCI63735.
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Research Article Oncology

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 Mob1aΔ/Δ1btr/+ or Mob1aΔ/+1btr/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

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Figure 3

Characterization of keratinocyte-specific Mob1a/1b double-homozygous mutant mice.

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Characterization of keratinocyte-specific Mob1a/1b double-homozygous mut...
(A–C) Features of 16-day-old Krt14CreERMob1afl/fl1btr/tr mice that were originally left untreated (control) or treated with tamoxifen (kDKO) at P1. (A) kDKO(P1) mice have a wrinkled-bear facial appearance (top left), ruffled, shaggy body hair (bottom left), abnormally large front paws (top right), and decreased survival (bottom right). (B) H&E-stained longitudinal and transverse sections of the back skin of the mice in A. kDKO(P1) mice show hyperplasia of IFE and HF. Scale bars: 50 μm. (C) kDKO(P1) mice show parakeratosis (reduced enucleation) in stratum corneum layers. Scale bar: 20 μm. (D) Immunohistochemical analyses of fat pad epidermis of the mice in A using Alexa Fluor 488–tagged Abs recognizing the indicated differentiation markers corresponding to a specific skin layer. DAPI, nuclei. Scale bar: 50 μm. (E) Immunohistochemical analyses of back skin of the mice in A using Abs recognizing the indicated skin layer markers. For top panels, cells were stained with Alexa Fluor 568–tagged anti-KRT14 Ab. DAPI, nuclei. Scale bars: 20 μm. For bottom panels, cells were stained with Alexa Fluor 488–tagged anti-Trichohyalin Ab and Fluor 568–tagged anti-KRT17 Ab. Scale bar: 50 μm. (F) H&E-stained longitudinal sections of skin from 42-day-old Krt14CreERMob1afl/fl1btr/tr mice that were left untreated (control) or treated with tamoxifen (kDKO) at P28. The kDKO(P28) mutant shows hyperplasia of IFE and HFs. Scale bar: 200 μm. Results shown are representative of at least 3 independent trials and at least 3 mice/group. Data are presented as the mean ± SEM.