Akatsuka Hisako, Kashikawa Tomohiro, Masuhara Kaori, Tokusanai Mizuki, Li Chenyang, Iida Yumi, Okada-Yamaguchi Chisa, Okada Yoshinori, Tanaka Masayuki, Suzuki Takahiro, Yamamoto Norio, Hozumi Katsuto, Tanaka Tomoaki, Nakaoka Hirofumi, Hosomichi Kazuyoshi, Hamaguchi Yu, Hamada Michiaki, Shiraishi Yoshiki, Kamiya Akihide, Nakamura Yoshihiko, Harada Kaito, Ibrahim Abd Aziz, Yahata Takashi, Ohtsuka Masato, Nakamura Naoya, Hosokawa Hiroyuki, Kimura Minoru, Inoue Ituro, Sato Takehito
Division of Host Defense Mechanism, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
Medical Science College Office, Tokai University, Isehara, Kanagawa 259-1193, Japan.
iScience. 2025 Jul 5;28(8):113054. doi: 10.1016/j.isci.2025.113054. eCollection 2025 Aug 15.
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 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 flox mice crossed with Rosa-Cre-ERT2-Tg mice. These inducible 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.
AMBRA1最初被报道通过自噬和细胞增殖控制对神经系统发育至关重要，它还通过与DDB1-Cullin4A/4B E3连接酶相互作用调节D型细胞周期蛋白的泛素化，从而发挥肿瘤抑制作用。我们通过对一个考登综合征家族进行外显子组分析，在其中鉴定出一个错义突变。患者型突变体显示DDB1结合减少且细胞周期蛋白D降解受损。为了研究AMBRA1的生理作用，我们构建了与Rosa-Cre-ERT2-Tg小鼠杂交的Ambra1基因条件性敲除小鼠。这些可诱导的条件性敲除小鼠体重增加、器官增大，S期进入增强，细胞周期蛋白D表达以细胞谱系或分化特异性方式升高。值得注意的是，它们对自发、辐射和化学诱导的恶性肿瘤的易感性显著更高。这些发现支持AMBRA1作为调节细胞周期蛋白D的肿瘤抑制因子的作用，尽管其他靶点可能也有贡献。
