Chinese Academy of Sciences JBC reveals new mechanism of cell cycle regulation
Researchers from the Institute of Microbiology of the Chinese Academy of Sciences have confirmed that Cyclin D1 does not depend on Cdk4, but promotes the cell cycle process by increasing the kinase activity of NDR1 / 2. The research was published in the July 29th Journal of Biochemistry (JBC). Researcher Xin Ye of the Institute of Microbiology, Chinese Academy of Sciences is the corresponding author of this Paper. The main research directions and contents include: cell cycle regulation mechanism, and molecular mechanism of virus and host interaction. Published more than 20 papers in Science, Neuron, PNAS, and other journals.
Cyclin / Cdks plays an important regulatory role in the cell cycle process by phosphorylating downstream substrates. Different Cyclin / Cdks perform their functions at different stages of the cell cycle. The Cyclin D1 / Cdk4 complex plays an important role in the G1 phase. It can phosphorylate Rb family proteins, making them unable to function as transcription repressors, thereby activating E2F-dependent transcription, promoting entry into the S phase, and initiating DNA synthesis. Cyclin D1 / Cdk4 can also phosphorylate Smad3 to inhibit its transcriptional activity and anti-proliferative function. Recently, studies have revealed that cyclin D1 / Cdk4 can phosphorylate the transcription factor FOXM1, improving its stability and activity in melanoma. To further explore the mechanism by which cyclin D1 / Cdk4 regulates cell cycle progression, the researchers used a TAP-labeled purification method to identify Cdk4 interacting proteins and discovered the NDR1 / 2 protein. Interestingly, when the researchers confirmed the interaction between NDR1 / 2 and cyclin D1 / Cdk4, it was observed that NDR1 / 2 can interact with cyclin D1 independently of Cdk4. But NDR1 / 2 and cyclin D1 / Cdk4 could not phosphorylate each other. In addition, the researchers found that NDR1 / 2 did not affect the kinase activity of cyclin D1 / Cdk4 phosphorylated GST-Rb. They confirmed that cyclin D1 but not Cdk4 promoted the kinase activity of NDR1 / 2.
The researchers also confirmed that cyclin D1 K112E, which cannot bind Cdk4, can also promote NDR1 / 2 kinase activity. In order to test whether cyclin D1 promotes G1 / S phase transition by promoting NDR1 / 2 kinase activity, they used cyclin D1 and cyclin D1 K112E tetracycline control system (tet-on) cell lines for flow cytometry analysis. Research data shows that both cyclin D1 and cyclin D1 K112E can promote G1 / S phase transition.
Importantly, the researchers found that inhibiting NDR1 / 2 can almost completely destroy the function of cyclin D1 K112E to promote G1 / S phase conversion. Consistent with this, they found that p21 protein levels were reduced in cells that overexpressed cyclin D1 K112E, but no effect was observed in the inhibition of NDR1 / 2. These findings reveal a new functional mechanism of cyclin D1: independent of Cdk4, it promotes the cell cycle process by increasing NDR kinase activity.
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