Cell Cycle Regulation Overview

Cell Cycle Regulation

• The cell cycle is a series of events that take place in a cell leading to its duplication.
• The cell cycle is tightly controlled by tumour suppressor genes to prevent uncontrolled cell growth.
• The protein products of tumour suppressor genes inhibit cell division.
• Two important tumour suppressor genes are RB1 and TP53.
• These two produce proteins Rb and p53 respectively.
• Cell cycle control is maintained by protein complexes composed of two subunits: cyclin (cyc) and cyclin-dependent kinase (cdk).
• Kinases are enzymes that inactivate/activate other proteins by phosphorylation.
• The concentration of cyclins fluctuates in the cell.
• The active form of cdks (cyc-cdk) can phosphorylate various proteins, leading to protein activation or inactivation, e.g. phosphorylation of G1/S transcription factors.
• The activity of cdks is regulated by degradation of cyclins by the proteasome.
• The proteasome is a giant protein complex that degrades short-lived proteins, such as cyclins and misfolded proteins.
• Proteins destined for degradation are first tagged with ubiquitin, a small regulatory protein.
• Addition of ubiquitin is facilitated by enzymes called ubiquitin ligases (E3 ligases).

Phases of the Cell Cycle

• The cell cycle consists of interphase and the mitotic phase.
• Interphase includes G1, S, and G2 phases.
• The mitotic phase (M) includes mitosis and cytokinesis.
• The figure 12.5 shows the schematic representation of the cell cycle.

Cell Cycle Checkpoints

• Checkpoints are control points in the cell cycle where stop and go ahead signals regulate the cell cycle.
• They control transitions between the phases.
• They ensure that certain processes have been completed, e.g. DNA replication and presence of growth factors, before another phase starts.
• Three important checkpoints are G1, G2, and M checkpoints.

G1 Checkpoint (Restriction Point)

• Occurs at the end of G1 phase.
• Checks for the presence of growth factors, cell size, and DNA damage.
• Controls the transition to the S phase (DNA replication).

G2 Checkpoint

• Controls the transition from the G2 phase to the M phase (mitosis).
• Checks for DNA damage and DNA replication completion.

M Checkpoint (Metaphase Checkpoint)

• Controls the transition through the stages of mitosis.
• Checks for correct chromosome alignment in the mitotic spindle during metaphase.

The Cell Cycle Control System

• The cell cycle is regulated by a molecular control system.
• Cytoplasmic molecules regulate progress through the cycle.
• Three major checkpoints are G1, G2, and M.
• The G1, G2, and M checkpoints regulate transitions from one phase to the next based on internal and external signal input.

Mitogens (Growth Factors)

• Growth factors stimulate other cells to divide.
• An example is PDGF (platelet-derived growth factor) which stimulates fibroblast growth in a wound.
• Removal of mitogen will result in reduction in the cyclin-cdk levels; cells won't pass the restriction point R and won't replicate.

Cell Cycle Control by Cyclins/Cdks

• Specific cyclins and cyclin-dependent kinases (Cdks) control different steps in the cell cycle.
• Each phase has specific cyclin-cdk complexes.

MPF (Mitosis Promoting Factor)

• The signal that sends cells into mitosis is called MPF (Mitosis Promoting Factor).
• MPF consists of a mitotic cyclin (cyclin A or cyclin B) and cdk-1.
• MPF induces the progression from G2 to M phase by a variety of reactions including phosphorylation, inactivation of anaphase promoting complex, phosphorylation of nuclear lamina, and fragmentation of the nuclear envelope.

Negative Regulation of MPF activity by APC

• APC (Anaphase Promoting Complex) is an E3 ubiquitin ligase that inactivates mitotic cyclins and hence MPF during interphase.
• Proteolysis of mitotic cyclins at the end of mitosis leads to a reduction of MPF activity.

The TP53 Gene

• The TP53 gene encodes for the p53 protein.
• The p53 protein detects DNA damage, inducing G1-G2 arrest, apoptosis, or DNA repair.
• Over 50% of cancers contain mutations in the TP53 gene.

Density-Dependent Inhibition and Anchorage Dependence

• Density-dependent inhibition means crowded cells stop dividing.
• Anchorage dependence means most animal cells must be attached to a substratum to divide.
• Cancer cells do not exhibit density-dependent inhibition or anchorage dependence; they continue to divide well beyond a single layer leading to clumps of overlapping cells.

Cancer Cells: Loss of Cell Cycle Control

• Cancer cells do not respond normally to the body's control mechanisms.
• They make their own growth factors or have always-ON signaling pathways.
• They exhibit abnormal cell cycle control and form tumors
• Benign tumors are not invasive and contained within a particular site
• Malignant tumors are invasive and can spread to other organs (metastasis).

Malignant Tumors

• Malignant tumors invade surrounding tissues and export cancer cells to other parts of the body; forming secondary tumors.

Cancer Cells’ Characteristics

• Cancer cells have specific characteristics including resisting cell death, sustaining proliferative signaling, evading growth suppressors, inducing angiogenesis, and enabling replicative immortality.

Challenges to Cancer Treatment

• Cancer treatment challenges arise from the diverse physiological pathways and tissue specificities within tumours.
• Intratumoral, intermetastatic and interpatient heterogeneity further complicates treatment strategies.
• Precision Oncology is one approach used.

Precision Oncology

• The science of using a patient's genetics to create a treatment plan targeted to the particular molecular characteristics of a specific cancer.
• A rapidly developing research area.

SBA Example 1

• At which cell cycle phase is MPF (mitosis promoting factor) active?
  • The correct answer is M phase.

SBA Example 2

• What does MPF consist of?
  • The correct answer is Cyc-A/cdk-1.

External Signals (Summary)

• Growth factors stimulate cell division.
• Other external signals include density-dependent inhibition (crowded cells stop dividing) and anchorage dependence (cells must be attached to a substratum in order to divide).

Explore the intricate mechanisms of cell cycle regulation and the role of tumour suppressor genes such as RB1 and TP53. Understand how cyclin-dependent kinases (cdks) interact with cyclins to control cell division. This quiz covers essential concepts necessary for comprehending cell biology and cancer development.