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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
Published on: May 3, 2018
Aberrant expression of cyclin D1 in cancer
Kazushi Inoue1, Elizabeth A Fry1
1Department of Pathology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157 USA.
Abstract:
Cyclin D1 binds and activates cyclin-dependent kinases 4/6 (Cdk4/6) to phosphorylate the retinoblastoma (RB) family proteins, relieving E2F/DPs from the negative restraint of RB proteins and histone deacetylases. The cyclin D-Cdk4/6 complexes activate cyclin E/Cdk2 through titration of the Cdk inhibitors p21Cip1/p27Kip1. Cyclin E/Cdk2 further phosphorylates RBs, thereby activating E2F/DPs, and cells enter the S phase of the cell cycle. Cyclin D-Cdk4/6 also phosphorylates MEP50 subunit of the protein arginine methyltransferase 5 (PRMT5), which cooperates with cyclin D1 to drive lymphomagenesis in vivo. Activated PRMPT5 causes arginine methylation of p53 to suppress expression of pro-apoptotic and anti-proliferative target genes, explaining the molecular mechanism for tumorigenesis. Cyclin D1 physically interacts with transcription factors such as estrogen receptor, androgen receptor, and Myb family proteins to regulate gene expression in Cdk-independent fashion. Dmp1 is a Myb-like protein that quenches the oncogenic signals from activated Ras or HER2 by inducing Arf/p53-dependent cell cycle arrest. Cyclin D1 binds to Dmp1α to activate both Arf and Ink4a promoters to induce cell cycle arrest or apoptosis in non-transformed cells to prevent them from neoplastic transformation. Dmp1-deficiency significantly accelerates mouse mammary tumorigenesis with reduced apoptosis and increased metastasis. Cyclin D1 interferes with ligand activation of PPARγ involved in cellular differentiation; it also physically interacts with histone deacetylases (HDACs) and p300 to repress gene expression. It has also been shown that cyclin D1 accelerates tumorigenesis through transcriptional activation of miR-17/20 and Dicer1 which, in turn, represses cyclin D1 expression. Identification of cyclin D1-binding proteins/promoters will be essential for further clarification of its biological activities.
Insights
Cyclin D1 drives cell cycle progression and tumorigenesis by activating kinases and interacting with various proteins. It also promotes cancer by suppressing apoptosis and enhancing proliferation, highlighting its complex role in cell regulation.
Area of Science:
- Molecular Biology
- Cell Cycle Regulation
- Cancer Biology
Background:
- Cyclin D1 is a key regulator of the cell cycle, controlling transitions through interactions with cyclin-dependent kinases (Cdks).
- Dysregulation of cyclin D1 is implicated in various cancers, underscoring its importance in cell proliferation and tumorigenesis.
- Understanding cyclin D1's binding partners and regulatory mechanisms is crucial for deciphering its multifaceted roles in normal and cancerous cells.
Purpose of the Study:
- To elucidate the molecular mechanisms by which cyclin D1 promotes cell cycle progression and tumorigenesis.
- To identify novel cyclin D1-binding proteins and their functional significance in cancer development.
- To explore both Cdk-dependent and Cdk-independent functions of cyclin D1 in cellular processes.
Main Methods:
- The study involved analyzing the interactions of cyclin D1 with cyclin-dependent kinases (Cdk4/6) and retinoblastoma (RB) proteins.
- Investigated the phosphorylation of MEP50 by cyclin D1-Cdk4/6 complexes and its effect on PRMT5 activity.
- Examined cyclin D1's interactions with transcription factors (estrogen receptor, androgen receptor, Myb) and its role in regulating gene expression, including its binding to Dmp1α.
Main Results:
- Cyclin D1-Cdk4/6 complexes phosphorylate RB proteins, promoting cell cycle entry and activating cyclin E/Cdk2.
- Cyclin D1 phosphorylates MEP50, activating PRMT5, which methylates p53, suppressing pro-apoptotic genes and driving lymphomagenesis.
- Cyclin D1 interacts with transcription factors and Dmp1α to regulate gene expression and induce cell cycle arrest or apoptosis, while its deficiency accelerates mammary tumorigenesis.
- Cyclin D1 also represses gene expression through interactions with HDACs and p300 and activates oncogenic microRNAs.
Conclusions:
- Cyclin D1 plays a critical role in cell cycle progression and tumorigenesis through diverse mechanisms, including kinase activation and protein-protein interactions.
- Its ability to suppress apoptosis and promote proliferation, coupled with its interactions with various cellular components, highlights its oncogenic potential.
- Further identification of cyclin D1-binding proteins and promoters is essential for a comprehensive understanding of its biological activities and therapeutic targeting.
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