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Phosphorylation of transcription factors and control of the cell cycle
1Institute of Molecular Medical Services, Palo Alto, California 94306, USA.
Abstract:
Protein phosphorylation has evolved as the most versatile posttranslational modification widely used by cells. Signal transduction pathways mediated by activation of MAP kinases and protein kinase C trigger the exit of cells from the quiscence (Go-->G1 transition). Indeed, binding of growth factors at the cell surface triggers their receptors, usually possessing a tyrosine kinase on the cytoplasmic side, to phosphorylate other molecules passing on the information sequentially to GRB2 protein, to p21ras, to c-Raf-1, to MAP kinase kinase, to MAP kinase, to p90rsk, to transcription factors. Activated PKC, MAP kinase, and pp90src can translocate to the nucleus where they phosphorylate a number of protein transcription regulators in a cell cycle-dependent manner or in response to cell stimulation for exit from quiescence. The cell cycle is mainly regulated by p34cdc2 or otherwise called cdc2 in association with cyclins B at G2/M and by Cdk2 in association with cyclins A, D1, and E at G1/S checkpoints; phosphorylation of histone H1 and lamins by cdc2 triggers chromosome assembly and nuclear envelope breakdown, respectively, as a prelude to mitosis. Cdc2 activities functioning as a G2/M regulator are controlled by its phosphorylation and dephosphorylation at Ser/Thr residues. MAP kinases might be the missing link in the chain connecting the Go to G1 transition with the cell cycle regulation, whereas phosphorylation of replication protein factors, retinoblastoma, and p53 might link the G1 to S transition with the control of DNA synthesis. A number of transcription factors are known to stimulate DNA replication, including p53, c-Myc, AP-1, Oct-1, T-antigen; the DNA binding activities of all these proteins and their interaction with other transcription factors are controlled by phosphorylation. The nuclear import of several proteins including NF kappa B, Dorsal, glucocorticoid receptor, ISGF3, rNFIL-6, T antigen, and the kinases PKC, MAP, and p90rsk, are dependent on their phosphorylation at specific sites. Histone phosphorylation stimulated at discrete stages of the cell cycle or in response to cAMP or other stimuli might induce profound changes in chromatin organization.
Insights
Protein phosphorylation, a key posttranslational modification, regulates cell cycle transitions. MAP kinases and protein kinase C are crucial for cell cycle entry and DNA replication control.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Protein phosphorylation is a versatile posttranslational modification essential for cellular signaling.
- Signal transduction pathways involving MAP kinases and protein kinase C (PKC) regulate cell cycle progression, particularly the transition from quiescence (G0) to the G1 phase.
- These pathways involve sequential phosphorylation events from cell surface receptors to transcription factors.
Purpose of the Study:
- To elucidate the role of protein phosphorylation in regulating cell cycle transitions.
- To highlight the involvement of specific kinases, such as MAP kinases and PKC, in controlling cell cycle entry and DNA replication.
- To explore the connection between G0-G1 transition, cell cycle regulation, and DNA synthesis control.
Main Methods:
- The study reviews existing literature on signal transduction pathways and protein phosphorylation.
- It analyzes the roles of specific kinases (MAP kinases, PKC, Cdk2, cdc2) and their substrates in cell cycle regulation.
- Focuses on phosphorylation-dependent regulation of transcription factors, nuclear import, and chromatin organization.
Main Results:
- MAP kinases and PKC activation trigger cell exit from quiescence (G0 to G1 transition).
- Specific kinases like cdc2 and Cdk2, in complex with cyclins, regulate G2/M and G1/S checkpoints, respectively, through phosphorylation of substrates like histone H1 and lamins.
- Phosphorylation of replication factors, retinoblastoma protein, and p53 links G1 to S transition with DNA synthesis control, while histone phosphorylation impacts chromatin organization.
Conclusions:
- MAP kinases may bridge the G0 to G1 transition with cell cycle regulation.
- Phosphorylation is a critical regulatory mechanism for transcription factors, nuclear import, and chromatin structure.
- Protein phosphorylation is central to controlling cell cycle progression, DNA replication, and cellular responses to stimuli.