Cell Cycle & Cell Division

Somatostatin (SST) is a peptide hormone that binds to somatostatin receptors (SSTR1–5). These receptors inhibit cell growth, among other cellular functions (1). Elevated SSTR2 expression inhibits cell growth by inducing apoptosis and cell cycle arrest and reducing epidermal growth factor receptor (EGFR) signaling (2).

The BTG/Tob protein family, which consists of six members, including TOB1, TOB2, BTG1, BTG2/PC3/TIS21, BTG3/ANA and BTG4/PC3B, are negative regulators of the cell cycle that help to prevent uncontrolled cell proliferation (3).

TOB1 expression suppresses the transcription of positive cell cycle regulators, including IL2, IL4, IFNg, cyclin E and cyclin A, inhibiting cell proliferation (4). BTG/TOB proteins also inhibit cell proliferation by potentially enhancing deadenylation. TOB2 promotes deadenylation by recruiting Caf1 deadenylase to the mRNA poly(A) tail. This recruitment occurs through the interaction of TOB2 with Caf1 and poly(A)-binding protein (PABP). BTG1 is another antiproliferative mediator whose expression peaks in the G0/G1 phases of the cell cycle and drops as cells move through G1. BTG2 negatively regulates the cell cycle checkpoint from the G1 to S phase by suppressing cyclin D1 promoter activity. BTG3 binds to transcription factor E2F1 to regulate cell proliferation and the G2 checkpoint (5). BTG4 induces G1 and G2 arrest in the cell cycle by targeting the CD1/CDK4 pathway, the cyclin E pathway or transcription factors PRMT1 and CAF-1 (6).

Cell cycle checkpoints are crucial regulatory mechanisms that ensure the proper progression of the cell cycle phases: G0, G1, S, G2 and M. These checkpoints monitor and verify the accuracy of critical cellular events, like reaching the appropriate cell size, integrity of DNA replication and repair and accuracy of chromosome segregation during mitosis (7).

There are several key cell cycle checkpoints. The G1 checkpoint ensures that the cell is ready for DNA synthesis by checking for cell size, nutrients, growth factors and DNA damage. The S checkpoint makes sure that DNA replication has been completed correctly without errors. The G2 checkpoint ensures that all chromosomes have been accurately replicated and checks for DNA damage before the cell enters mitosis. The M checkpoint ensures that all of the chromosomes are properly attached to the spindle fibers before anaphase begins.

Failure of these checkpoints to function properly can lead to severe consequences, such as uncontrolled cell division, which can result in cancer. Properly functioning checkpoints can trigger apoptosis (programmed cell death) as a protective measure to eliminate cells with significant damage, preventing the spread of potential cancerous cells (7).

G1 is the phase where the cell prepares to divide. It then moves into the S phase, where the cell creates additional copies of the DNA (8). In the G1 phase, growth-dependent CDK activity stimulates DNA replication and triggers the transition from G1 to the S phase. CDK activation also sets off a positive feedback loop that leads to increased CDK activity, initiating genome-wide transcriptional changes to ensure cell division (9).

The G2 checkpoint maintains genomic stability by preventing DNA-damaged cells from entering mitosis. This mechanism stops the proliferation of damaged cells and allows for DNA repair (10).

The serine/threonine kinase complex CDK1/Cyclin B is the principal regulator of the transition from G2 to M. CDK1 levels remain constant throughout the cell cycle, while Cyclin B levels peak during early mitosis and drop to their lowest at the end of M phase. Cyclin B levels are regulated at the transcriptional level through transcription factors NF-Y, FOXM1 and B-MYB and by proteolysis through the E3 ubiquitin ligase APC. Activated Cdk1-Cyclin B phosphorylates mitotic substrates, including Wee1/Myt1 and Cdc25, to regulate G2 to M transition (11).

Cyclins are a family of regulatory proteins that play a crucial role in controlling the progression of cells through the cell cycle. They function as regulatory subunits of cyclin-dependent kinases (CDKs), which are enzymes that drive regulate cell cycle progression by phosphorylating and activating specific target substrates. One critical target, for example, is the retinoblastoma (Rb) protein, which, when phosphorylated, allows the cell to progress from the G1 phase to the S phase of the cell cycle. (12)

In mammals, there are five major classes of cyclins involved in cell cycle regulation: cyclins A, B, C, D and E. D-type cyclins (cyclin D1, D2 and D3) are crucial during the G1 phase, where they form complexes with CDK4 and CDK6 to drive the cell past the G1 checkpoint. Cyclin E, in association with CDK2, facilitates the transition from G1 to S phase, initiating DNA replication. Cyclin A binds to CDK2 during the S phase and later to CDK1, playing pivotal roles in both S phase progression and the G2/M transition. Cyclin B, in a complex with CDK1, is essential for the initiation of mitosis. Cyclin C, although less well-characterized, is known to play a role in regulating the G1 phase in association with CDK3. (12)

The expression levels of cyclins vary throughout the cell cycle, with each type appearing at specific stages to activate the corresponding CDKs. This regulated expression ensures that the cell cycle progresses in a controlled manner and prevents uncontrolled cell division, which could lead to cancer.

High mobility group box 1 (HMGB1) is a non-histone nuclear protein that plays many roles depending on its location within the cell. In the nucleus, HMGB1 interacts with DNA and histones to maintain the structure and function of chromosomes and regulate transcription, DNA repair, genome stability and other cellular processes. In the cytoplasm, it promotes autophagy by binding to the BECN1 protein (13). In the context of the cell cycle, HMGB1 can interact with p53 to modulate its transcriptional activity, thereby influencing cell cycle arrest and apoptosis (14).

Polo-like kinase 1 (PLK1) is a serine-threonine protein kinase that regulates the mitotic cycle (15). It is necessary for regulating many processes involved in cell division, including genome stability, spindle assembly, centrosome maturation, checkpoint recovery, DNA damage response, cytokinesis and apoptosis. Plk1, for instance, phosphorylates NudC to regulate cytokinesis (16).

CHK proteins are activated in response to DNA damage. Checkpoint kinase 1 (Chk1) mediates the G1/S transition, S phase, mitotic entry and spindle checkpoint in the M phase. On the other hand, checkpoint kinase 2 (CHK2) activity arrests the cell cycle at G1/S and G2/M (17, 18). CHK proteins phosphorylate and inhibit Cdc25 phosphatases, preventing CDC2 activation and thereby halting cell cycle progression. CHK2 and CHK1 also regulate the cell cycle by phosphorylating P53 and upregulating P212, further inhibiting cell cycle progression (19).

Telomeres are protective chromosome ends that shorten with cell division until they reach a point where cells undergo senescence or apoptosis to prevent genetic irregularities. This mechanism, although protective, speeds up tissue degradation and leads to age-related disorders (20).

Telomerase is an enzyme that attaches telomere repeat sequences to chromosome ends, stopping telomeres from reaching a limit that triggers senescence and crisis. Telomerase activity is significant in cellular aging and cancer due to its role in maintaining telomere length.

Telomerase signaling is absent in most normal somatic cells but is activated in 85% of cancer cells, allowing these cells to bypass senescence and divide indefinitely. This replicative immortality is a hallmark of many cancers, making telomerase a potential target for cancer therapies (21).