LECTURE 19 Cell Cycle and MAPK Pathway Notes

  • Human Body and Cell Renewal

    • The human body consists of approximately 40 trillion cells.
    • Every second, hundreds of thousands of cells undergo death and replacement.
    • Regulation of this process is crucial for health:
    • If cell death outpaces replacement, it can lead to issues like a leaky intestinal wall.
    • Conversely, excessive division may indicate cancer due to erroneous reproduction.

  • Cell Cycle Overview

    • Cell Cycle: The schedule responsible for maintaining a healthy cell count, encompassing several phases each with checkpoints for quality control.
    • At checkpoints, cells undergo security checks to ensure conditions are right for division.
    • If issues arise, cells can undergo programmed cell death (apoptosis).

  • G0 Phase

    • Cells not actively dividing enter the G0 phase, remaining metabolically active.
    • Typical functions during this phase include:
    • Muscle cells: Contracting
    • Neurons: Transducing signals
    • Secretory cells: Producing hormones
    • Some differentiated cells stay in G0, while others, like certain skin cells, can divide.

  • Phases of the Cell Cycle

    • G1 Phase:

    • Cell checks for size, nutrients, growth factors, and DNA integrity.

    • Division is energetically costly, so energy levels are evaluated.

    • S Phase:

    • Each chromosome is copied to ensure daughter cells receive a full gene set.

    • G2 Phase:

    • The cell grows and produces necessary proteins.

    • At a checkpoint, it checks for size and completion of DNA replication.

    • M Phase:

    • Final checks on mitotic spindle assembly and chromosome alignment occur.

    • If passed, the cell divides into two daughter cells, either continuing division or specializing.

  • Cell Function and Protein Expression

    • Different phases require distinct protein expression patterns.
    • Change in protein expression can result from extracellular growth factors.

  • MAPK Pathway

    • The MAPK pathway allows cells to convey extracellular signals to the nucleus.

    • EGF (Epidermal Growth Factor):

    • Binds to EGFR (a receptor tyrosine kinase), facilitating receptor dimerization.

    • Dimerization activates intracellular domains to recruit signaling molecules for further cascades:

      • GRB2: Mediator for receptor signal to intracellular proteins.
      • SOS: A docking site for RAS.

    • RAS Activation:

    • RAS exchanges GDP for GTP, activating itself.

    • Activated RAS can amplify signals by activating multiple downstream proteins.

  • RAF Activation

    • Inactive RAF binds 14-3-3 proteins which inhibit its activation.

    • To activate RAF:

    • Remove the inhibitory 14-3-3 protein.

    • Requires SRC for phosphorylation.

    • Nanoclusters form from active RAS and RAF, recruiting downstream signaling proteins.

  • Downstream Signaling

    • Activated RAF subsequently activates MEK and ERK.
    • ERS's Role:
    • Translocates to the nucleus and activates MYC, a transcription factor.
    • MYC promotes gene expression by increasing its half-life and forming a dimer with MAX, which binds DNA.

  • Transcription Activation

    • MYC-MAX binding influences gene expression by recruiting histone acetyltransferases.

    • Histone acetylation promotes DNA access for transcription machinery, allowing gene expression.

    • The MAPK pathway illustrates how an extracellular signal, such as a growth factor, can drastically alter a cell's protein expression and function.