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The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5.

ABSTRACT: 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 through an unknown mechanism. Here, we found that regulated protein degradation via the E3 ubiquitin ligase UBR5 is responsible for Rb's concentration drop in G1. UBR5 knockout cells have increased Rb concentration in early G1, exhibited a lower G1/S transition rate, and are more sensitive to inhibition of Cdk4/6. This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies.

SUBMITTER: Zhang S

PROVIDER: S-EPMC10592979 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5.

Zhang Shuyuan S Valenzuela Lucas Fuentes LF Zatulovskiy Evgeny E Mangiante Lise L Curtis Christina C Skotheim Jan M JM

bioRxiv : the preprint server for biology 20240412

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 thi ...[more]

PMID: 37873473

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Project description:Fully differentiated mature smooth muscle cells (SMCs) are characterized by the presence of a unique repertoire of smooth muscle-specific proteins. Although previous studies have shown myocardin to be a critical transcription factor for stimulating expression of smooth muscle-specific genes, the mechanisms regulating myocardin activity are still poorly understood. We used a yeast two-hybrid screen with myocardin as bait to search for factors that may regulate the transcriptional activity of the myocardin. From this screen we identified a HECT domain-containing protein UBR5 (ubiquitin protein ligase E3 component n-recognin 5) as a myocardin-binding protein. Previous studies have shown that HECT domain-containing proteins are ubiquitin E3 ligases that play an important role in protein degradation. UBR5 has, however, also been shown to regulate transcription independent of its E3 ligase activity. In the current study we demonstrated that UBR5 localized in the nuclei of SMCs and forms a complex with myocardin in vivo and in vitro. We also show that UBR5 specifically enhanced trans-activation of smooth muscle-specific promoters by the myocardin family of proteins. In addition, UBR5 significantly augmented the ability of myocardin to induce expression of endogenous SMC marker genes independent on its E3 ligase function. Conversely, depletion of endogenous UBR5 by small interfering RNA in fibroblast cells attenuated myocardin-induced smooth muscle-specific gene expression, and UBR5 knockdown in SMCs resulted in down-regulation of smooth muscle-specific genes. Furthermore, we found that UBR5 can attenuate myocardin protein degradation resulting in increased myocardin protein expression without affecting myocardin mRNA expression. The effects of UBR5 on myocardin requires only the HECT and UBR1 domains of UBR5. This study reveals an unexpected role for the ubiquitin E3 ligase UBR5 as an activator of smooth muscle differentiation through its ability to stabilize myocardin protein.

Dataset Information

The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5.

Publications

The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5.

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