GO:1900087 positive regulation of G1/S transition of mitotic cell cycle: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1900087 describes any signaling pathway that increases or activates a cyclin-dependent protein kinase to promote the switch from G1 phase to S phase of the mitotic cell cycle.
• The G1/S transition is driven by CDK4/6-cyclin D and CDK2-cyclin E complexes, which phosphorylate RB1 and unleash E2F transcription factors.
• Positive regulators include growth factor signaling, nutrient-sensing pathways such as TOR, and phosphatases like the Cdc25 family that remove inhibitory phosphates.
• Dysregulation of G1/S transition is a hallmark of cancer; cell cycle-related gene signatures stratify breast cancer subtypes and predict prognosis.
• The circadian clock and DNA damage response intersect with G1/S control, influencing treatment resistance in cancer.
• Experimental dissection of G1/S regulation benefits from CRISPR knockout, point mutation, knock-in, and overexpression models, combined with omics and imaging.
Description
The transition from G1 phase to S phase is a decisive commitment point in the mitotic cell cycle, where cells decide whether to replicate their DNA or exit the cycle. GO:1900087, positive regulation of G1/S transition of mitotic cell cycle, captures the signaling events that activate cyclin-dependent kinases (CDKs) to drive this switch. Understanding these positive regulatory inputs is fundamental to cell biology, cancer research, and developmental studies, because misregulated G1/S progression can lead to uncontrolled proliferation or genomic instability. This article synthesizes authoritative QuickGO annotation and verified PubMed literature to provide a research-grade overview of the term, its molecular players, and experimental strategies for interrogation.
positive regulation of G1/S transition of mitotic cell cycle At A Glance
| GO ID | GO:1900087 |
|---|---|
| GO term | positive regulation of G1/S transition of mitotic cell cycle |
| Ontology | biological_process |
| Synonym | activation of G1/S transition of mitotic cell cycle; up regulation of G1/S transition of mitotic cell cycle; up-regulation of G1/S transition of mitotic cell cycle; upregulation of G1/S transition of mitotic cell cycle |
| Major function | Activation of cyclin-dependent kinases to promote G1-to-S phase progression |
| Key kinases | CDK4, CDK6, CDK2 |
| Key cyclins | Cyclin D, Cyclin E |
| Key substrates | RB1, E2F transcription factors |
| Regulatory phosphatases | Cdc25 family (CDC25A, CDC25B, CDC25C) |
What Is GO:1900087?
GO:1900087 is a biological process term defined as any signaling pathway that increases or activates a cell cycle cyclin-dependent protein kinase to modulate the switch from G1 phase to S phase of the mitotic cell cycle. In other words, it encompasses the positive regulatory inputs—such as growth factor signaling, nutrient sensing, and phosphatase activity—that promote CDK activation and drive cells past the G1 restriction point into S phase.
Why Is positive regulation of G1/S transition of mitotic cell cycle Important in Cell Biology?
Positive regulation of the G1/S transition is central to normal development and tissue homeostasis, and its dysregulation is a common feature of cancer and other proliferative disorders. Because this process integrates growth factor signaling, nutrient availability, and cell cycle checkpoints, it serves as a focal point for understanding how cells coordinate proliferation with environmental cues. Targeting positive regulators of G1/S, such as CDK4/6, has become a validated therapeutic strategy in oncology, underscoring the translational relevance of this GO term.
• Controls the commitment point for DNA replication and cell division.
• Integrates growth factor and nutrient signals via TOR and other pathways.
• Dysregulation leads to uncontrolled proliferation in cancer.
• Cell cycle-related gene signatures stratify breast cancer subtypes and predict outcomes.
• Circadian clock and DNA damage response intersect with G1/S control, affecting treatment resistance.
• Cdc25 phosphatases are critical activators of CDKs at G1/S.
• Yeast models reveal conserved splicing factors like Cdc40 in G1/S progression.
• Network modules of cell cycle regulators can be predicted from protein abundance data.
• Plant TOR signaling controls cell cycle progression, highlighting evolutionary conservation.
• Endoreduplication genes like GaTOP6B influence cell cycle variants in plants.
What Happens During positive regulation of G1/S transition of mitotic cell cycle?
Growth Factor Signaling and CDK Activation
In simple terms: Growth factors tell the cell it is time to divide by turning on the enzymes that start DNA replication.
Positive regulation begins when mitogenic growth factors bind to receptors and activate signaling cascades that induce cyclin D expression and CDK4/6 activity. This leads to phosphorylation of RB1, releasing E2F transcription factors that drive S-phase gene expression. The TOR pathway further integrates nutrient status to promote cell cycle entry in plants and other organisms.
Cdc25 Phosphatase-Mediated CDK Activation
In simple terms: Special enzymes remove inhibitory marks from CDKs, switching them on.
The Cdc25 family of phosphatases removes inhibitory phosphates from CDKs, thereby activating them and promoting G1/S transition. Cdc25A is particularly important for CDK2 activation, while Cdc25B and Cdc25C function later in the cycle. Their activity is tightly regulated to ensure proper timing of CDK activation.
RB1 Phosphorylation and E2F Release
In simple terms: A gatekeeper protein is phosphorylated, allowing transcription factors to turn on DNA replication genes.
Active CDK4/6-cyclin D and CDK2-cyclin E complexes phosphorylate the RB1 protein, disrupting its interaction with E2F transcription factors. Free E2F then activates genes required for DNA synthesis and S-phase progression. This phosphorylation cascade is a key positive regulatory step in the G1/S transition.
Integration with Circadian and DNA Damage Responses
In simple terms: The cell's internal clock and DNA repair systems also influence when the cell decides to divide.
The circadian clock and DNA damage response pathways intersect with G1/S regulation, affecting cell cycle progression and treatment resistance. For example, circadian clock components can modulate the expression of cell cycle genes, while DNA damage checkpoints can halt the transition to allow repair. This integration ensures that proliferation occurs only under favorable conditions.
Conserved Mechanisms in Model Organisms
In simple terms: Similar control mechanisms are found in yeast and plants, helping researchers study the process.
In yeast, the cell cycle/splicing factor Cdc40 plays a role in the G1/S transition, demonstrating conservation of regulatory mechanisms. In plants, TOR signaling controls cell cycle progression, and endoreduplication genes like GaTOP6B regulate trichome branching, linking cell cycle variants to development. These models provide insights into the fundamental principles of G1/S positive regulation.
Key Genes Involved in GO:1900087 positive regulation of G1/S transition of mitotic cell cycle
The following genes and proteins are central to the positive regulation of the G1/S transition, based on verified literature and pathway knowledge.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CDK4 | Phosphorylates RB1 to promote G1/S transition | Target of CDK4/6 inhibitors in cancer |
| CDK6 | Phosphorylates RB1 to promote G1/S transition | Target of CDK4/6 inhibitors in cancer |
| CDK2 | Complexes with cyclin E to drive S-phase entry | Key kinase for G1/S transition |
| CCND1 | Cyclin D1, activates CDK4/6 | Overexpressed in many cancers |
| CCNE1 | Cyclin E1, activates CDK2 | Amplified in breast and other cancers |
| RB1 | Retinoblastoma protein, gatekeeper of G1/S | Tumor suppressor, frequently mutated |
| E2F1 | Transcription factor released by RB1 phosphorylation | Drives S-phase gene expression |
| CDC25A | Phosphatase that activates CDK2 | Oncogene, overexpressed in cancers |
| CDC25B | Phosphatase that activates CDKs | Involved in G2/M and G1/S |
| CDC25C | Phosphatase that activates CDKs | Regulates mitotic entry |
| TOR | Nutrient-sensing kinase that promotes cell cycle entry | Conserved regulator in plants and animals |
| CDC40 | Splicing factor involved in G1/S transition | Yeast model for cell cycle control |
| GaTOP6B | Endoreduplication gene affecting trichome branching | Plant cell cycle variant |
| CDKN2A | Inhibits CDK4/6, negative regulator of G1/S | Frequently deleted in cancer |
| CCND2 | Cyclin D2, activates CDK4/6 | Cell cycle-related gene in breast cancer |
| CCNE2 | Cyclin E2, activates CDK2 | Cell cycle-related gene in breast cancer |
| MCM2 | DNA replication licensing factor | Marker of S-phase entry |
How Is positive regulation of G1/S transition of mitotic cell cycle Regulated?
Positive regulation of the G1/S transition is controlled by multiple layers of regulation. The TOR signaling pathway integrates nutrient and energy status to promote cell cycle entry, as shown in plants. Growth factor signaling induces cyclin D expression, while CDK inhibitors such as p27 and p21 can block CDK activity. The Cdc25 phosphatases are themselves regulated by phosphorylation and localization, ensuring timely CDK activation. Additionally, the circadian clock and DNA damage response pathways can modulate G1/S progression, influencing cell fate decisions.
positive regulation of G1/S transition of mitotic cell cycle and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CDK4 | Breast cancer, liposarcoma | Knockout or point mutation in cancer cell lines |
| CCND1 | Breast cancer, lymphoma | Overexpression in breast cancer models |
| RB1 | Retinoblastoma, osteosarcoma | Knockout in retinal or bone cancer cells |
| CDC25A | Various cancers | Overexpression or knockout in cancer cell lines |
| CDKN2A | Melanoma, pancreatic cancer | Knockout in melanoma cell lines |
Cancer
Dysregulation of positive G1/S regulators is a hallmark of cancer. Overexpression of cyclin D1, CDK4/6, or loss of RB1 leads to uncontrolled proliferation. Cell cycle-related gene signatures, including CDK4, CDK6, CCND1, and CCNE1, are used to stratify breast cancer subtypes and predict prognosis. CDK4/6 inhibitors have become standard therapy for hormone receptor-positive breast cancer, highlighting the clinical relevance of this pathway.
Treatment Resistance and Circadian Clock
The circadian clock 'death-loop' intersects with the DNA damage response and G1/S transition, contributing to cancer treatment resistance. Circadian disruption can alter cell cycle progression and reduce the efficacy of DNA-damaging agents. Targeting the interplay between circadian rhythms and G1/S regulation may offer new therapeutic strategies.
Sepsis and Immune Cell Proliferation
Key genes in sepsis, identified through stochastic perturbation analysis, include cell cycle-related genes, suggesting that G1/S regulation is important in immune cell responses during infection. Dysregulated proliferation of immune cells can contribute to sepsis pathology.
From positive regulation of G1/S transition of mitotic cell cycle-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of CDK4 block G1/S transition? | CRISPR knockout of CDK4 in cancer cell lines |
| Does a specific point mutation in RB1 affect E2F binding? | Point mutation knock-in of RB1 in cells |
| Does overexpression of cyclin D1 drive proliferation? | Overexpression of CCND1 in breast cancer cells |
| Where is CDK2 localized during G1/S? | Tagged knock-in of CDK2 with fluorescent protein |
| Does Cdc25A inhibition arrest cells in G1? | Knockout or point mutation of CDC25A |
| How does TOR signaling affect G1/S in plants? | Knockout of TOR in Arabidopsis or crop models |
How to Study the positive regulation of G1/S transition of mitotic cell cycle Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Gene expression changes | Identify cell cycle gene signatures |
| Proteomics | Protein abundance and modifications | Predict network modules of cell cycle regulators |
| Flow cytometry | DNA content and cell cycle phase | Validate G1/S arrest or progression |
| Live-cell imaging | Real-time dynamics of CDK activity | Track G1/S transition in single cells |
| CRISPR knockout screen | Loss-of-function phenotypes | Discover positive regulators of G1/S |
| CRISPR activation screen | Gain-of-function phenotypes | Identify genes that drive G1/S |
| Yeast genetics | Conserved cell cycle mechanisms | Study Cdc40 and other regulators |
| Plant transformation | Cell cycle in plant development | Analyze TOR and endoreduplication genes |
Transcriptomic and Proteomic Profiling
RNA-seq and proteomics can quantify expression changes in cell cycle genes during G1/S transition. For example, integrated analysis of cell cycle-related genes in breast cancer used transcriptomic data to identify key regulators. Relative protein abundance statistics can predict network modules of cell cycle regulators.
Flow Cytometry and Imaging
Flow cytometry with DNA dyes measures cell cycle distribution, while live-cell imaging of fluorescently tagged CDKs or cyclins tracks G1/S progression in real time. These methods are essential for validating positive regulators identified by genetic screens.
CRISPR Screens and Functional Genomics
Genome-wide CRISPR knockout or activation screens can identify positive regulators of G1/S transition. Stochastic perturbation analysis has been used to identify key genes in sepsis, including cell cycle-related genes. Such screens are powerful for discovering novel regulators.
Model Organism Studies
Yeast and plant models provide conserved insights into G1/S regulation. For instance, the yeast splicing factor Cdc40 was identified as a G1/S regulator, and plant TOR signaling controls cell cycle progression. Endoreduplication genes like GaTOP6B affect trichome branching, linking cell cycle to development.
How CRISPR Can Be Used to Study GO:1900087 positive regulation of G1/S transition of mitotic cell cycle
Knockout
CRISPR knockout of positive regulators such as CDK4, CDK6, or CCND1 can confirm their requirement for G1/S transition. For example, knocking out CDK4 in cancer cell lines leads to G1 arrest and reduced proliferation. Knockout models are also useful for studying conserved genes like CDC40 in yeast.
Point Mutation
Point mutations can dissect specific phosphorylation sites or catalytic residues. For instance, mutating the catalytic cysteine of CDC25A can abolish its phosphatase activity and block G1/S transition. Point mutation knock-in of RB1 can test the importance of individual phosphorylation sites for E2F binding.
Knock-in
Knock-in of tagged versions of CDKs or cyclins allows real-time tracking of their localization and dynamics during G1/S. Fluorescent knock-in of CDK2 or cyclin E can reveal when and where they are activated. Knock-in of disease-associated mutations, such as in RB1, can model cancer predisposition.
Overexpression
Overexpression of cyclin D1 or CDK4 can drive cells past the G1 restriction point, mimicking oncogenic events. Overexpression models are valuable for testing whether a candidate gene is sufficient to promote G1/S transition. In plants, overexpression of GaTOP6B affects trichome branching, linking cell cycle to development.
How EDITGENE Supports positive regulation of G1/S transition of mitotic cell cycle Research
Researchers studying positive regulation of G1/S transition of mitotic cell cycle-related genes often need to determine whether a candidate gene is causally involved in driving or restraining the transition. EDITGENE provides a comprehensive suite of CRISPR services to enable such functional studies with precision and reproducibility.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of G1/S transition of mitotic cell cycle research.
Frequently Asked Questions About positive regulation of G1/S transition of mitotic cell cycle
What is GO:1900087?
GO:1900087 is a Gene Ontology biological process term for any signaling pathway that increases or activates a cyclin-dependent protein kinase to promote the G1-to-S phase transition of the mitotic cell cycle.
What genes are involved in positive regulation of G1/S transition?
Key genes include CDK4, CDK6, CDK2, CCND1, CCNE1, RB1, E2F1, and the CDC25 family of phosphatases.
How is the G1/S transition regulated?
It is regulated by growth factor signaling, nutrient-sensing pathways like TOR, and phosphatases such as Cdc25 that activate CDKs.
Why is the G1/S transition important in cancer?
Dysregulation of G1/S regulators leads to uncontrolled proliferation, and CDK4/6 inhibitors are used to treat breast cancer.
What methods are used to study G1/S transition?
Common methods include RNA-seq, proteomics, flow cytometry, live-cell imaging, and CRISPR screens.
What is the role of Cdc25 in G1/S transition?
Cdc25 phosphatases remove inhibitory phosphates from CDKs, activating them to drive G1/S progression.
How does TOR signaling affect G1/S transition?
TOR integrates nutrient signals to promote cell cycle entry, as shown in plant models.
What CRISPR models are available for G1/S research?
Knockout, point mutation, knock-in, and overexpression models can be generated for genes like CDK4, RB1, and CDC25A.
Can circadian clock affect G1/S transition?
Yes, the circadian clock intersects with DNA damage response and G1/S regulation, influencing treatment resistance.
What is the role of RB1 in G1/S transition?
RB1 is phosphorylated by CDKs, releasing E2F transcription factors that drive S-phase gene expression.
Conclusion
GO:1900087, positive regulation of G1/S transition of mitotic cell cycle, encompasses the signaling pathways that activate CDKs to drive cells into S phase. This process is fundamental to normal proliferation and is frequently dysregulated in cancer and other diseases. Understanding its molecular players and regulatory mechanisms provides opportunities for therapeutic intervention and biomarker discovery. EDITGENE offers comprehensive CRISPR services to support functional studies of these regulators, from knockout to overexpression and library screening.
References
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- 4. Vainshelbaum NM et al.. 2022. Role of the Circadian Clock "Death-Loop" in the DNA Damage Response Underpinning Cancer Treatment Resistance.. Cells 11(5) PMID: 35269502
- 5. Kaplan Y et al.. 2007. A role for the yeast cell cycle/splicing factor Cdc40 in the G1/S transition.. Curr Genet 51(2):123-40 PMID: 17171376
- 6. Oguz C et al.. 2017. Predicting network modules of cell cycle regulators using relative protein abundance statistics.. BMC Syst Biol 11(1):30 PMID: 28241833
- 7. Song J et al.. 2024. A cotton endoreduplication gene, GaTOP6B, regulates trichome branching development.. Plant Physiol Biochem 214:108888 PMID: 38954944
- 8. Li Z et al.. 2017. Identification of key genes in Gram‑positive and Gram‑negative sepsis using stochastic perturbation.. Mol Med Rep 16(3):3133-3146 PMID: 28714002
