Q: How do CHK proteins contribute to cell cycle checkpoint control?

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).

Question 1

What is the antiproliferative role of somatostatin receptor 2 in cell cycle regulation?

Accepted Answer

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).

Question 2

What is the role of BTG family proteins in regulating the cell cycle?

Accepted Answer

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).

Question 3

What are cell cycle checkpoints?

Accepted Answer

The cell cycle phases, G0, G1, S, G2 and M, are regulated by checkpoints that monitor the progression of critical events in the cell cycle, including reaching the appropriate cell size, chromosome replication and integrity and accurate chromosome segregation during mitosis (7). If the checkpoints don't work properly, it can cause different results, including uncontrolled cell division, leading to cancer or cell death, as a protective response against cancer (7).

Question 4

How is the G1/S checkpoint regulated in the cell cycle?

Accepted Answer

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).

Question 5

What mechanisms are involved in the regulation of the G2/M DNA damage checkpoint?

Accepted Answer

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).

Question 6

How do cyclins regulate cell cycle progression?

Accepted Answer

Cyclins are regulatory subunits of CDKs. They regulate cell cycle progression by phosphorylating and activating specific target substrates involved in different cell cycle stages, such as Rb protein (12). Cyclins A, B, C, D and E are the four major classes of mammalian cyclins, all of which play different roles in regulating cell cycle progression. For instance, the cyclin D binds to Cdk4 or Cdk6 to regulate the shift from G0 to the G1 phase (12).

Question 7

What role does HMGB1 signaling play in the cell cycle and cellular processes?

Accepted Answer

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).

Question 8

What are the mitotic roles of polo-like kinase in cell division?

Accepted Answer

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).

Question 9

How do CHK proteins contribute to cell cycle checkpoint control?

Accepted Answer

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).

Question 10

What is the significance of telomerase signaling in cellular aging and cancer?

Accepted Answer

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).

Cell Cycle & Cell Division

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