Cancer

• mitogens stimulate cell division
• growth factors stimulate cellular growth
• survival factors suppress apoptosis
• the G1 chekcpoint is when the cell commits to entering the cell cycle and chromosome duplication
• the conditions needed to pass the G1 checkpoint are sufficient nutrients, sister chromatid separation from the previous mitosis, no detectable DNA damage, and has reached the critical threshold size
• the G2 checkpoint triggers early mitotic events that lead to chromosome alignment in the metaphase plate
• the conditions for the G2 checkpoint are complete and accurate DNA replication, no DNA damage, and the cell must have reached its minimum size
• the M checkpoint (occurs in the transition between metaphase and anaphase) stimulates sister chromatid separation, resulting in the completion of mitosis
• the conditions to pass the m checkpoint are the mitotic spindles must be assembled at opposite poles and the chromosomes must be aligned and properly attached to the spindle MTs
• the cell cycle control system is dependent on cyclin dependent protein kinases (Cdks)
• Cdks are proteins that initiate or regulate major cell cycle events
• cyclins are proteins that regulate Cdk activity
• G1 Cdk activates gene regulatory factors and uses G1/S and S cyclins. it is involved in DNA synthesis and chromosome duplication
• G1/S- Cdks drive progression through the G1 checkpoint. it initiates centrosome duplication. they unleash a wave of S-Cdk activity and trigger cell cycle entry
• S-Cdks activate DNA helicase
• Cdk associates with the M cyclin by

  1. binding to the cyclin to create partial activation
  2. CAK phosphorylates the Cdk to fully activate the enzyme
  3. Wee1 phosphorylation inhibits Cdk activity
• M-Cdk drives entry into mitosis by

  1. inducing assembly of the mitotic spindle
  2. triggers chromosome condensation
  3. promotes breakdown of the nuclear envelope
  4. promotes rearrangement of the actin cytoskeleton and Golgi
• Cdk inhibitor proteins (CKI) inactivates Cdk by changing the shape of the active site
• p53 is a transcriptional regulator that stimulates the transcription of p21, which arrests the cell cycle in G1. mutations in p53 can cause uncontrolled cell division
• proto-oncogenes code for positive cell cycle regulators that may be overactive in cancer
• tumor suppressor genes code for negative regulators in the cell cycle and may be less active in cancer
• mutations in DNA maintenance genes can cause genetic instability, which can lead to greater accumulation of mutations
• hydrophobic ligands can travel across the plasma membrane and bind to receptors found in the cytoplasm
• once the ligand binds, a conformational change in the receptor exposes a DNA-binding site on the receptor protein
• estrogen binds to the estrogen receptor (ER), which regulates transcription of target genes by binding the the estrogen response element (ERE) and recruiting coregulatory proteins (CoRegs).
• the nuclear progesterone receptor (PR) is a part of the steroid subgroup of transcription factors, which activate gene transcription and protein formation.
• Once progesterone crosses the membrane, it binds to the ligand binding domain of nuclear PR, causing conformational change.
• the PR steroid complex then dimerizes and interferes with other transcription factors and promoters within target genes.
• ion channel coupled receptors open to allow an influx of ions into the cell when the ligand binds to the extracellular region of the channel
• enzyme coupled receptors get activated when ligands promote dimerization, resulting in the interaction and activation of cytoplasmic domains
• g protein coupled receptors have seven transmembrane domains. when the receptor binds its ligand, another set of intracellular proteins (G proteins) are activated
• Ras acts like a molecular switch and its activity is determined by the presence of GTP (on) or GDP (off). it is turned on when GEFs exchange GDP form GTP. it is turned off when GAPs increase the rate of hydrolysis of bound GTP.
• cancer's development and progression are likely to be a series of changes in the activity of cell cycle regulators
• tumor cells can have features that are heritable (somatic mutations and epigenetic changes)
• somatic mutations are detectable abnormalities in the DNA sequence that distinguish them from normal cells surrounding the tumor
• epigenetic changes result in the modification of chromatin structures without altering a cell's DNA sequence
• cancer cells can divide more because they express telomerase at higher levels
• telomerase has a function RNA component (hTERC) which serves as a template for synthesis and a catalytic protein (hTERT) with reverse transcriptase activity
• epithelial to mesenchymal transition (EMT) allows cancer cells to escape from the place of origin and metastasize.
• EMT steps

  1. downregulate expression of transmembrane adhesion molecules in tight junctions, adherens junctions, hemidesmosomes, and desmosomes
  2. Upregulate expression of cell surface receptors that are needed for migration
  3. Upregulate expression of proteases (allows the cells to break through the basal lamina and carve a path of migration through the proteins of the underlying connective tissue)