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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 Article has an altmetric score of 11

Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice

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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 6

Characterization of skin cancers of Mob1-deficient mice and human trichilemmal carcinomas.

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Characterization of skin cancers of Mob1-deficient mice and human trichi...
(A) H&E-stained sections of representative tumors from Mob1aΔ/Δ1btr/+ or Mob1aΔ/+1btr/tr mice showing: (top left) characteristic trichilemmal keratinization (yellow arrows; also in right); (bottom left) atypical and highly mitotic cells; and (right) continuity with the epidermis. Scale bars: 50 μm (left); 500 μm (right). (B) Immunostaining of tumors from Mob1aΔ/Δ1btr/+ or Mob1aΔ/+1btr/tr mice to detect the indicated skin markers. White arrows, cancerous lesions; yellow arrow, nontumorous HF. Scale bar: 200 μm. (C) Immunoblot of total extracts of control and kDKO(P1) keratinocytes to detect ERK and AKT activation as well as the HF morphogenesis proteins GLI2 (FL; full length), LEF1 and HES1. β-Actin, loading control. (D) Immunostaining to detect GLI2 in HFs from control or kDKO(P1) mice. Scale bar: 25 μm. (E) Immunoblot to detect GLI2 in total extracts of control keratinocytes transfected with scramble siRNA (Control siSc) or Gli2 siRNA (Control siGli2), as well as in samples of 4 trichilemmal carcinomas (Tumor 1, 2, 3, 4) from kDKO(P1) mice. (F) H&E staining of a human trichilemmal carcinoma viewed at low (scale bar: 200 μm) or high magnification (scale bar: 50 μm). (G) Immunostaining to detect YAP1 and MOB1A/1B in human trichilemmal carcinomas and nearby noncancerous tissues. Top: Both noncancerous and trichilemmal carcinoma (T) tissues can be seen in low-magnification images. Bottom: High-magnification images of human trichilemmal carcinomas. Scale bars: 100 μm. Results shown are representative of at least 3 independent trials and at least 3 mice/group.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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