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