CRL4AMBRA1 is a master regulator of D-type cyclins
| Autor: | Francesco Boccalatte, Giacomo Milletti, Arnaldo A. Arbini, Sarah Keegan, Yeon-Tae Jeong, Francesco Cecconi, Sorasicha Nithikasem, Luca Busino, Francesca Nazio, Yik Siu, Gergely Róna, Nan Zhou, Emiliano Maiani, Alfie O’sullivan, Michele Pagano, Daniele Simoneschi, Andrew A. Wang, Drew R. Jones, David Fenyö, Shaowen Jiang, Valentina Cianfanelli |
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| Přispěvatelé: | Simoneschi, Daniele, Rona, Gergely, Zhou, Nan, Jeong, Yeon-Tae, Jiang, Shaowen, Milletti, Giacomo, Arbini, Arnaldo A, O'Sullivan, Alfie, Wang, Andrew A, Nithikasem, Sorasicha, Keegan, Sarah, Siu, Yik, Cianfanelli, Valentina, Maiani, Emiliano, Nazio, Francesca, Cecconi, Francesco, Boccalatte, Francesco, Fenyö, David, Jones, Drew R, Busino, Luca, Pagano, Michele |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Settore BIO/06 Cell division Regulator Hyperphosphorylation Biology law.invention Gene Knockout Techniques Mice HEK293 Cell law Neoplasms Animals Cyclin D2 Humans CRISPR-Cas System Cyclin D1 Genes Tumor Suppressor Cyclin D3 Cyclin Adaptor Proteins Signal Transducing Multidisciplinary Animal Ubiquitin Cyclin-dependent kinase 2 Cyclin-Dependent Kinase 2 Gene Knockout Technique Signal Transducing Cyclin-Dependent Kinase 4 Adaptor Proteins Cyclin-Dependent Kinase 6 HCT116 Cells Cell biology Ubiquitin ligase HEK293 Cells HCT116 Cell biology.protein Neoplasm Suppressor Female Cyclin-dependent kinase 6 CRISPR-Cas Systems Cell Division Human |
| Popis: | D-type cyclins are central regulators of the cell division cycle and are among the most frequently deregulated therapeutic targets in human cancer1, but the mechanisms that regulate their turnover are still being debated2,3. Here, by combining biochemical and genetics studies in somatic cells, we identify CRL4AMBRA1 (also known as CRL4DCAF3) as the ubiquitin ligase that targets all three D-type cyclins for degradation. During development, loss of Ambra1 induces the accumulation of D-type cyclins and retinoblastoma (RB) hyperphosphorylation and hyperproliferation, and results in defects of the nervous system that are reduced by treating pregnant mice with the FDA-approved CDK4 and CDK6 (CDK4/6) inhibitor abemaciclib. Moreover, AMBRA1 acts as a tumour suppressor in mouse models and low AMBRA1 mRNA levels are predictive of poor survival in cancer patients. Cancer hotspot mutations in D-type cyclins abrogate their binding to AMBRA1 and induce their stabilization. Finally, a whole-genome, CRISPR–Cas9 screen identified AMBRA1 as a regulator of the response to CDK4/6 inhibition. Loss of AMBRA1 reduces sensitivity to CDK4/6 inhibitors by promoting the formation of complexes of D-type cyclins with CDK2. Collectively, our results reveal the molecular mechanism that controls the stability of D-type cyclins during cell-cycle progression, in development and in human cancer, and implicate AMBRA1 as a critical regulator of the RB pathway. Biochemical and genetics studies identify CRL4AMBRA1 as the ubiquitin ligase that has a key role in regulating the stability of D-type cyclins during cell-cycle progression. |
| Databáze: | OpenAIRE |
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