Cell Cycle Regulation & Cancer

Cell Cycle Regulation and Cancer

Learning Outcomes

  • 11C: Explain how cell cycle control systems and cell cycle checkpoints regulate appropriate progression through the cell cycle.

  • 11D: Use examples to describe how changes in cell cycle checkpoints or a mutation in a signal system molecule could lead to uncontrolled cell division and contribute to cancer.

Cell Cycle Control System

  • Overview of control checkpoints within the cell cycle:

    • G1 checkpoint

    • S phase

    • G2 checkpoint

    • M checkpoint

G1 Checkpoint

  • Questions considered at G1 checkpoint:

    • Is the cell of sufficient size?

    • Have proper signals from the environment been received?

  • If Yes: Decision to duplicate chromosomes and centrosomes.

S Phase

  • Chromosome and centrosome duplication occurs.

G2 Checkpoint

  • Questions considered at G2 checkpoint:

    • Have the chromosomes been completely duplicated?

  • If Yes: Decision to enter mitosis.

M Checkpoint

  • Questions considered at M checkpoint:

    • Have all chromosomes arrived and aligned at the metaphase plate?

  • If Yes: Decision to initiate anaphase.

Cell Cycle Regulators

  • Cyclins:

    • Family of structurally and functionally related proteins required for cell cycle function in eukaryotes.

  • CDKs (Cyclin-dependent kinases):

    • Family of structurally and functionally related proteins that add phosphate to target proteins, thus changing protein activity.

    • Cyclin:CDK Interaction:

    • Cyclin dictates which target protein will be phosphorylated by the CDK.

    • MPF (Maturation Promoting Factor or M-phase Promoting Factor): Promotes the transition from G2 to M phase.

Function of Cyclin-dependent Kinases (CDK)

  • CDKs control the cell cycle by phosphorylating other proteins.

  • Phosphorylation initiates a chain of events that activates certain transcription factors, promoting the transcription of genes whose functions are required at that stage of the cell cycle.

Regulation of MPF Activity

  • Graphical Representation:

    • MPF activity vs. Cyclin concentration over time:

    • Key Point: Increases occur during specific phases of the cell cycle.

Cell Cycle Checkpoints

  • Review Reference: International Journal of Molecular Sciences 21(6):1960.

  • Additional insights on Cyclins and CDKs.

Effect of Platelet-Derived Growth Factor (PDGF) on Cell Division

  1. Cells are transferred to culture vessels with a basic growth medium (glucose, amino acids, salts, antibiotics).

  2. PDGF is added to half of the vessels; incubation at 37°C for 24 hours occurs.

  3. Observation:

    • In the control (without PDGF), cells fail to divide, emphasizing the importance of growth factors.

Anchorage Dependence and Density-Dependent Inhibition

  • Anchorage Dependence: Cells require a surface for division.

  • Density-Dependent Inhibition:

    • Cells form a single layer and divide to fill gaps before stopping.

  • Comparison of Normal vs. Cancer Cells:

    • Normal mammalian cells vs. Cancer cells.

Loss of Cell Cycle Controls in Cancer Cells

  • Characteristics of Cancer Cells:

    • Do not respond to normal cell cycle regulation signals.

    • Do not require growth factors for growth and division; can produce their own or convey signals without them.

    • Exhibit an abnormal cell cycle control system.

Tumor Formation

  • Cells that can divide indefinitely undergo transformation, forming tumors (masses of abnormal cells).

  • Benign Tumors: Abnormal cells remain localized.

  • Malignant Tumors:

    • Invade surrounding tissues and can undergo metastasis, spreading cancer cells to other parts of the body and forming additional tumors.

  • Treatment Options:

    • Localized tumors may be treated with high-energy radiation.

    • Metastatic cancers may be treated with chemotherapies targeting the cell cycle.

Characteristics of Cancer Cells

  • Key Features:

    • Uncontrolled cell growth.

    • Accumulation and propagation of mutants.

    • Ability to invade and disrupt local and distant tissues.

    • Loss of density-dependent inhibition and anchorage dependence.

Genetic Basis of Cancer

  • Oncogenes: Contribute to unregulated cell growth and division.

    • Proto-oncogenes: Normal genes that, when mutated, convert into oncogenes (e.g., Ras).

  • Tumor Suppressor Genes: Normally inhibit cell division and repair damaged DNA (e.g., p53).

    • Act as brakes to the cell cycle.

Involved Genes and Pathways

  • List of genes related to cancer (e.g., EGFR, KIT, ERBB2, MET, FGFR, PDGFRA, FLT3).

  • Cancer is considered a disease of signaling pathways.

The Role of Proto-Oncogenes in Signaling Pathways

  • First Messenger: Example- signaling molecule (e.g., epinephrine) activates G protein-coupled receptor (GPCR).

  • Sequence of changes resulting in active protein kinases and cellular responses via second messengers (cAMP).

Role of Ras Protein in the Cell Cycle

  • Activate pathways leading to normal cell division when stimulated by growth factor.

  • Mutated Ras: Can lead to increased cell division without the presence of growth factors.

Impact of Protein Kinases on Cell Cycle Regulation

  • Normal Functioning: Active form of p53 inhibits cell division by preventing replication of damaged DNA (UV light example).

  • Mutant p53: Loss of inhibitory function leads to increased cell division and cancer development.

Cancer Statistics

  • Estimated Deaths and New Cases by Cancer Type:

    • Data categorized by gender and type of cancer (e.g., prostate, breast, lung).

Growth and Metastasis of Malignant Tumors

  • Process of tumor growth from a single cancer cell.

  • Spread mechanisms include lymphatic and blood vessels to further metastasize.

Cancer Research and Treatment Approaches

  • Overview of precision medicine in cancer involving various inhibitors affecting multiple pathways.

The Multistep Model of Cancer Development

  • Multiple mutations are usually needed for the development of cancer; incidence increases with age.

  • Common Characteristics: Cancer cells typically have at least one active oncogene and mutations in tumor suppressor genes (e.g., p53, APC).

Case Study: Colorectal Cancer Development

  1. Loss of tumor suppressor gene (e.g., APC).

  2. Activation of oncogene (e.g., Ras).

  3. Loss of further tumor suppressor genes (e.g., p53).

  4. Development of benign growths (adenomas) leading to malignant tumors (carcinomas).

Learning Objectives to Review

  • Identification of different checkpoints in the cell cycle.

  • Understanding of cyclins and CDKs, and characteristics of cancer cells.

  • Explanation of oncogenes and tumor suppressor genes, conversion of proto-oncogenes to oncogenes, and mutations in Ras and p53 leading to cancer.

Vocabulary - Cancer

  • Key terms to understand:

    • Cell cycle checkpoints

    • Cancer

    • Oncogenes (Ras)

    • Tumor suppressor genes (p53)

    • Density-dependent inhibition

    • Anchorage dependence

    • Benign tumors

    • Malignant tumors

    • Metastasis

    • Cyclin-dependent kinases (CDK)

    • Cyclins

Suggested Reading Resources

  • Textbook Concepts:

    • Concept 9.3: The eukaryotic cell cycle is regulated by a molecular control system.

    • Concept 16.3: Abnormal regulation of genes that affect the cell cycle can lead to cancer.