The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5
Summary Mammalian cells make the decision to divide at the G1/S transition in response to diverse signals impinging on the retinoblastoma protein Rb, a cell cycle inhibitor and tumor suppressor. Rb is inhibited by two parallel pathways. In the canonical pathway, Cyclin D-Cdk4/6 kinase complexes phosphorylate and inactivate Rb. In the second, recently discovered pathway, Rb’s concentration decreases during G1 to promote cells progressing through the G1/S transition. However, the mechanisms underlying this second pathway are unknown. Here, we found that Rb’s concentration drop in G1 and recovery in S/G2 is controlled by phosphorylation-dependent protein degradation. In early G1 phase, un- and hypo-phosphorylated Rb is targeted by the E3 ligase UBR5.UBR5knockout cells have higher Rb concentrations in early G1, exhibit a lower G1/S transition rate, and are more sensitive to Cdk4/6 inhibition. This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 15. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Shuyuan [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.10.03.560768 |
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XBI041070070 |
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| 520 | |a Summary Mammalian cells make the decision to divide at the G1/S transition in response to diverse signals impinging on the retinoblastoma protein Rb, a cell cycle inhibitor and tumor suppressor. Rb is inhibited by two parallel pathways. In the canonical pathway, Cyclin D-Cdk4/6 kinase complexes phosphorylate and inactivate Rb. In the second, recently discovered pathway, Rb’s concentration decreases during G1 to promote cells progressing through the G1/S transition. However, the mechanisms underlying this second pathway are unknown. Here, we found that Rb’s concentration drop in G1 and recovery in S/G2 is controlled by phosphorylation-dependent protein degradation. In early G1 phase, un- and hypo-phosphorylated Rb is targeted by the E3 ligase UBR5.UBR5knockout cells have higher Rb concentrations in early G1, exhibit a lower G1/S transition rate, and are more sensitive to Cdk4/6 inhibition. This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies. | ||
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| 700 | 1 | |a Mangiante, Lise |e verfasserin |4 aut | |
| 700 | 1 | |a Curtis, Christina |e verfasserin |4 aut | |
| 700 | 1 | |a Skotheim, Jan M. |e verfasserin |4 aut | |
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