| First Author | Akatsuka H | Year | 2025 |
| Journal | iScience | Volume | 28 |
| Issue | 8 | Pages | 113054 |
| PubMed ID | 40734673 | Mgi Jnum | J:370350 |
| Mgi Id | MGI:8227616 | Doi | 10.1016/j.isci.2025.113054 |
| Citation | Akatsuka H, et al. (2025) Molecular and genetic evidence for the role of AMBRA1 in suppressing S-phase entry and tumorigenesis. iScience 28(8):113054 |
| abstractText | 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 AMBRA1 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 Ambra1 flox mice crossed with Rosa-Cre-ERT2-Tg mice. These inducible Ambra1 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. |
