Molecular and genetic evidence for the role of AMBRA1 in suppressing S-phase entry and tumorigenesis
AMBRA1, which was initially reported to be essential for nervous system development via autophagy and cell proliferation control, also functions as a tumor suppressor by regulating the ubiquitination of D-type cyclins through interaction with DDB1-Cullin4A/4 B E3 ligase. We had identified a missense mutation in <i>AMBRA1</i> through exome analysis of a family with Cowden syndrome. The patient-type mutant showed reduced DDB1 binding and impaired cyclin D degradation. To investigate the physiological role of AMBRA1, we generated <i>Ambra1</i> flox mice crossed with Rosa-Cre-ERT2-Tg mice. These inducible <i>Ambra1</i> conditional knock out mice exhibited increased body weight, organ size, and enhanced S phase entry, with elevated cyclin D expression in a cell lineage- or differentiation-specific manner. Notably, their susceptibility to spontaneous, radiation-, and chemically induced malignancies was significantly higher. These findings support the role of AMBRA1 as a tumor suppressor that regulates cyclin Ds, although other targets may also contribute.
Authors
- Kazuyoshi Hosomichi (ORCID: https://orcid.org/0000-0003-2712-1825)
- Yumi Iida
- Yoshiki Shiraishi (ORCID: https://orcid.org/0000-0001-5275-6318)
- Michiaki Hamada (ORCID: https://orcid.org/0000-0001-9466-1034)
- Tomoaki Tanaka (ORCID: https://orcid.org/0000-0002-9753-4273)
- Yu Hamaguchi
- Takehito Sato
- Takahiro Suzuki (ORCID: https://orcid.org/0000-0002-7949-5477)
- Masato Ohtsuka (ORCID: https://orcid.org/0000-0002-6952-4238)
- Mizuki Tokusanai
- Chenyang Li (ORCID: https://orcid.org/0000-0002-9144-5827)
- Yoshihiko Nakamura (ORCID: https://orcid.org/0000-0002-2297-2885)
- Kaito Harada (ORCID: https://orcid.org/0000-0002-8462-7550)
- Kaori Masuhara (ORCID: https://orcid.org/0000-0002-6648-2431)
- Katsuto Hozumi (ORCID: https://orcid.org/0000-0002-7685-6927)
- Akihide Kamiya (ORCID: https://orcid.org/0000-0002-2552-4236)
- Norio Yamamoto (ORCID: https://orcid.org/0000-0001-8924-0710)
- Naoya Nakamura (ORCID: https://orcid.org/0000-0003-4332-5254)
- Hirofumi Nakaoka (ORCID: https://orcid.org/0000-0002-8454-1159)
- Abd Aziz Ibrahim (ORCID: https://orcid.org/0000-0003-1374-1089)
- Hiroyuki Hosokawa (ORCID: https://orcid.org/0000-0002-9592-2889)
- Hisako Akatsuka (ORCID: https://orcid.org/0000-0001-6094-4757)
- Takashi Yahata (ORCID: https://orcid.org/0000-0002-9332-0358)
- Tomohiro Kashikawa (ORCID: https://orcid.org/0009-0001-9632-2850)
- Ituro Inoue (ORCID: https://orcid.org/0000-0003-1706-8493)
- Masayuki Tanaka (ORCID: https://orcid.org/0000-0002-8682-8719)
- Minoru Kimura (ORCID: https://orcid.org/0000-0001-7026-419X)
- Yoshinori Okada
- Chisa Okada-Yamaguchi
Institutions
- Kanazawa University (JP)
- National Institute of Genetics (JP)
- Tokai University (JP)
- Tokyo University of Pharmacy and Life Sciences (JP)
- Waseda University (JP)
- Chiba University (JP)
- Sasaki Institute (JP)
- Soka University (JP)
Publication Details
- Journal
- iScience
- Published
- 2025-07-05
- DOI
- https://doi.org/10.1016/j.isci.2025.113054
- Citations
- 1
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.81