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How Does Growth Factor Influence The Cell Cycle?

Researchers study the intricacies of the cellular processes to be able to manipulate the clinicopathologic factors that affect the bodily processes. This is to address disorders, especially those associated with abnormalities in metabolic processes such as human cancers. One of the factors being studied is the growth factors and their effect on cell cycle processes.

So how does growth factor influence the cell cycle? The presence of growth factors induces cell cycle progression. The presence of growth factors induces the cells to exit the G0 cell cycle phase or quiescent phase and enter the succeeding cell cycle stages for cellular proliferation.

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The Cell Cycle Stages 

The cell cycle is a multistep process involved in cell proliferation, in which daughter cells are produced as a result. The cell cycle includes the phases G1 (Gap 1), S (Synthesis), and G2 (Gap 2), which are collectively called the interphase, and the M phase or mitosis. Cells may restart the cell cycle or exit it and go to the G0 or quiescent phase.

  • G1 Phase – Gap 1 or G1 phase is the phase where cell growth occurs. It’s the phase of the cell cycle where the cell prepares for DNA replication. This is done by increasing the cell size and producing the necessary enzymes and nutrients for the succeeding processes. External factors such as environmental cues, stress, and metabolic cues are interpreted by the cells for them to determine if they’ll be working towards self-renewal, differentiation, or death.
  • S Phase – Synthesis or S phase is the stage of the cell cycle where DNA is replicated. Two sister chromatids exist in this phase to ensure the doubling of the DNA content of the cells. This phase is also the phase of the lowest protein and gene activity, except for histones which are associated with DNA replication.
  • G2 Phase – Gap 2 or G2 phase is another phase where the cell grows, this time in preparation for cell division or mitosis. Organelles and proteins develop in this phase, along with the production of proteins and lipids necessary for their development.
  • M Phase – M phase or mitosis is the phase where cell division occurs. Included in this phase are the stages namely prophase (where chromosome condensation, centrosome separation, and nuclear membrane breakdown occurs), prometaphase (where the metaphase plate where the chromosomes will align on the next stage is established) metaphase (where chromosomes align in an equatorial plate), anaphase (where sister chromatids separate through the shortening of kinetochore microtubules), and telophase and cytokinesis (where chromosomes move towards separate poles and divide into the two daughter cells).
  • G0 Phase – G0 phase or quiescent phase is the phase of cell cycle arrest. It’s the phase where cells exit the cell cycle where cells retain cell viability and function without undergoing cell division.

G0 To S Interval And Its Regulation By Growth Factors 

The cellular functions that growth factors regulate include cell migration, cell survival, cell cycle progression, and differentiation. Growth factors regulate the cell cycle by initiating various signaling pathways. These signaling pathways are mediated by the binding of growth factors into its corresponding epidermal growth factor receptor, and include the following:

  • Ras/Erk pathway – In this pathway, the phosphorylated epidermal growth factor receptor induces a cascade of recruitment events to activate Ras, which in turn activates Raf. Raf then phosphorylates and activates the mitogen-activated protein kinase, which in turn activates Erk. Erk then promotes the activation and nuclear translocation of RSK, which exerts effects on c-Fos and SRF. Meanwhile, Erk itself also translocates in the nucleus and activates c-Fos and Elk1.
  • PI3K/Akt pathway – Upon binding of the ligand to its corresponding EGFR, PI3K generates phosphatidylinositol-3,4,5-triphosphate (PIP3) by phosphorylating phosphatidylinositol-4,5-bisphosphate (PIP2). In turn, proteins are recruited, including Akt which function in activating a series of events that lead to the prevention of cell death. Inhibitors of this pathway that work on different steps of the pathway include PTEN, PDK1, and mTORC2.

The only portion where growth factor concentrations affect the regulation of cell cycle is the portion between G0 and S phase, denoted as G0 up to an R point. The growth factor induces the transition of cells from G0 to their entry to the cell cycle. 

Its significance is shown when, for instance, a cell is grown in a medium without growth factors leading to the cultured cell staying at the G0 phase. Similarly, a cultured cell past the restriction (R) point no longer needs any growth factor, in that it will proceed to its cellular processes regardless of the concentrations of growth factor present. 

An important component of the R point is the phosphorylation of Rb (retinoblastoma protein, a classic tumor suppressor protein, the abnormality of which results in the development of retinoblastoma in a mammalian cell). This cell cycle process is promoted by growth factors through the regulation of Cdk activity. 

Growth factors increase the levels of cyclins and decrease the levels of Cdk inhibitors. Moreover, the regulation of cyclin-dependent kinase activity of complexes joined by p27Kip1 is different, in that p27Kip1 promotes the activity of cyclin D1/Cdk4,6 while it inhibits the activity of cyclin E/Cdk2.

The key components of cell cycle regulation affected by growth factors are the cyclin D1 and p27Kip1.

The “Two-Wave” Hypothesis Of Growth Factor-Stimulated Signaling 

The idea behind the “two-wave” hypothesis is that even in the continuous delivery of exogenous growth factors, signaling in the G1 phase occurs in two waves. The first wave in this growth factor-stimulated signaling is transient, while the second wave is sustained.

  • Transient first wave – The first wave of growth factor-stimulated signaling events does not persist beyond 60 minutes. This may be due to the half-life of the growth factor receptor, the presence of enzymes that metabolize the PI3K lipid products, and the expression of genes that oppose the effects of the signaling enzymes.
  • Sustained second wave – The sustained second wave occurs 4 hours after the transient first wave. This is detected in the accumulation of PI3K products 3-7 hours after platelet-derived growth factor (PDGF) stimulation, which in turn is required for PDGF-dependent DNA synthesis.

Similarly, there are three steps in growth factor-dependent signaling, namely:

  • 1st step: binding of growth factor to the cell surface receptor 
  • 2nd step: activation of the receptor’s kinase activity 
  • 3rd step: recruitment and activation of signaling enzymes 

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Checkpoints Of Cell Cycle

Cell cycle analysis is done through the observation of cell cycle processes such as post-translational modifications, structural biology, and enzyme kinetics. It revealed the molecular details of phase progression of the cell cycle and showed that cell cycle regulation occurs through different checkpoints such as cell size control, DNA damage responses, monitoring DNA replication, S-M dependency, and the mitotic spindle checkpoint.

1) Cell Size Control

Cells must exactly double their contents before they proceed to the succeeding stages of the cell cycle. Due to this, daughter cells that are large enough proceed towards the succeeding stages at a faster rate than the smaller daughter cells. The distribution in the cell cycle of these checkpoints and the response of the cell cycle to the cell size control varies depending on the species and cell type.

There are two hypotheses on the control of cell growth. The first of these hypotheses is that there’s a ribosomal protein that acts as a “translational sizer”, the levels of which increase together with increasing cell size then regulate the cell cycle upon reaching a certain amount. This hypothesis reflects the idea that nutritional status correlates with translational activity, in that nutrition controls ribosome biogenesis.

Another hypothesis on cell size control is via monitoring of cell geometry, observed in the fission yeast S. pombe. In this yeast species, there exists a protein called Pom1 that regulates the Cdr1-Cdr2-Wee1-Cdc2 axis, by inhibiting cell cycle progression. However, upon reaching a certain length, Pom1 can no longer influence this complex, leading to the phase progression towards the M phase.

2) DNA Damage Responses

Cells experience damage in their DNA through different mechanisms, which may be intrinsic or extrinsic. An example of intrinsic sources is DNA replication errors while an example of extrinsic sources is from carcinogenic chemicals. 

Regardless of these differences in acquiring DNA damage, the response of cells to these damages, in association with cell cycle phase progression, is the same, highly conserved from yeast cells into mammalian cells. 

This highly conserved pathway is the Chk1 pathway, which is activated in all known forms of DNA damage. Since the DNA lesions are different, this raises the idea that this pathway works through a common intermediate, the single-stranded DNA coated by replication protein A (RPA). 

Cells with damaged DNA recruit Chk1, which then is phosphorylated by ATR in humans, resulting in the cessation of phase progression in the cells. Inversely, dephosphorylation of Chk1 is done to induce the progression of cells towards mitosis, through type 1 phosphatases.

3) Monitoring DNA Replication

It must be ensured that lesions must be repaired during the G1 and G2 phases and that replication won’t occur in their presence. It must also be ensured during the S phase that replication only occurs once every cycle. 

Upon blockage to progression brought by the lesions and the prevention of a repetitive replication, the replisome (the proteins that carry out DNA replication) is stabilized to prevent replication during blockage and allow resumption of replication upon its removal.

Replisome stabilization is a function of the intra-S-phase checkpoint, known as Chk2 in humans. This process is done through the phosphorylation or autophosphorylation of the components namely Mrc1 (mediator of the replication checkpoint), ATR, Cds1/Chk2, and several other subunits including the MCM helicase.

4) S-M Dependency

In humans, one round of replication per cell cycle is maintained to ensure that proper ploidy (or the number of chromosomes) is maintained in the cell. S-M dependency ensures that ploidy won’t be increased or decreased in humans, where only euploidy is safely tolerated. 

In cells where ploidy is increased, such as in fission yeasts, mitosis is bypassed by these cells due to mechanisms such as degradation of Cdt1, defective Cdc6, constitutive (continuous expression) replication origin firing, and absence of mitotic cyclins.

5) The Mitotic Spindle Checkpoint

The mitotic spindle checkpoint works in a way similar to the DNA replication checkpoint described above; that is, before proceeding to the next phases of the cell cycle, components work to repair defects while other components block the transition to the next phases. 

More specifically, this checkpoint makes sure to prevent the activation of APCCdc20 if certain conditions haven’t been met yet such as kinetochores not yet occupying spindle microtubules or not enough tension present upon attachment of the kinetochores.

Proteins involved in this checkpoint include:

  • Mad2 (mitotic arrest deficient) – This protein inhibits the activity of Cdc20 which is responsible for the activation of APC that allows the phase progression towards anaphase.
  • Polo, Aurora, and NIMA-related (Nek) kinases – These proteins are responsible for regulating the production of spindle fibers and monitoring and correcting the defects of formation of these fibers.

6) Integrins

Integrins also play a role in cell cycle progression by mediating the attachment of cells to extracellular matrix (ECM) proteins such as fibronectin and collagen. This adhesion allows the signaling pathways induced by growth factors to occur, and suspension of the cells such that adhesion doesn’t happen results in the inhibition of cell cycle progression. In other words, integrins and growth factors work synergistically as cell cycle regulators that allow cell cycle to proceed.

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Regulation of cell proliferation occurs through the regulation of the cell cycle. Cell cycle regulators include regulatory proteins and growth factors, which are involved in the processes associated with the checkpoints of the cell cycle. These processes are the ones exploited to develop medical innovations.

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