PHRD5015 Lecture 19 - What is Cancer?

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PHRD5015 Lecture 19 - What is Cancer?
2013-11-11 03:10:39
PHRD5015 cancer

PHRD5015 cancer
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  1. NIH definition of cancer
    • 1) abnormal cells divide without control
    • and
    • 2) are able to invade other tissues
  2. transformed cells invade other tissues
  3. 6 hallmarks of cancer
    • 1) sustaining proliferative signaling
    • 2) evading growth suppressors
    • 3) activating invasion and metastasis
    • 4) enabling replicative immortality
    • 5) inducing angiogenesis
    • 6) resisting cell death
  4. genes that promote cancer
  5. what happens to oncogenes that make them contribute to the cancer phenotype?
    • become permanently active or
    • are overexpressed
  6. typical jobs oncogenes perform (2)
    • 1) cell growth circuitry
    • 2) factors that promote cellular survival/migration
  7. tumor suppressor genes
    • mutated/deleted in cancer cells
    • sensors of cell damage or genes that promote apoptosis
    • "gate keepers"
  8. examples of tumor suppressor genes (2)
    • 1) p53
    • 2) Rb
  9. when cells have reached their doubling limit (plateau)
    the loss of the proliferative ability of a cell associated with age
  10. PDM
    population doubling mean
  11. what types of damage contributes to senescence? (2)
    • 1) oxidative damage
    • 2) DNA damage
  12. cells grown in ____ (normal/high/low) oxygen reach senescence sooner than cells grown in _____ (normal/high/low) oxygen.
    • normal
    • low
  13. what types of DNA damage can trigger senescence? (2)
    • 1) loss of telomeres
    • 2) triggering DNA damage checkpoint in cell cycle
  14. "replication clock" that lies at the end of chromosomes
  15. loop structures that are several thousand bp's long, that shield DNA ends so chromosomes don't fuse together
  16. characteristics of telomere sequence (2)
    • 1) repetitive
    • 2) consists of several thousand repeats of a 6bp sequence
  17. how cell division is limited in a normal cell
    RNA primer that starts polymerase copying is degraded during each replication
  18. when the cell loses enough telomere sequence, and can't protect chromosome ends, but continues to try to divide
  19. effect of Crisis
    unprotected DNA end can fuse with other ends, causing massive damage: the breakage-fusion-bridge cycle
  20. enzyme that copies and extends the telomere
  21. hTERT
    • human telomerase reverse transcriptase
    • multiple subunits contained in telomerase
  22. what occurs when hTERT is introduced into cells just entering in the crisis stage
    • allows cells to continue to grow
    • -> hTERT is growth limiting factor
  23. expressed in cancer cells to evade crisis & divide forever
  24. 2 mechanisms by which cell division is strictly limited
    • 1) senescence
    • 2) crisis
  25. breaks the circuit between growth factor receptors and proliferation
  26. result of Crisis
    cells lose telomeres, and undergo massive DNA rearrangements and usually die from apoptosis
  27. stage in which cells are not dividing
  28. stage in which cell is preparing for cell division
  29. cell remains responsive to both inducing and inhibiting signals until this point
    restriction point
  30. after the restriction point, the cell will not respond to these signals
    inhibitory signals
  31. G1/S checkpoint
    • just before DNA synthesis
    • cell checks itself for damage
  32. phase during which the cell copies its DNA
    S phase
  33. phase during which the cell prepares for cell division
  34. phase during which the cell undergoes mitosis
    M phase
  35. what occurs at each checkpoint in the cell cycle?
    the cell makes sure that its DNA is not damaged before proceeding
  36. p53 characteristics (3)
    • 1) central sensor of damage
    • 2) moves cell into apoptosis if genome can't be repaired
    • 3) is a TF - promotes repair or apoptosis
  37. gene that MUST be mutated/deleted for transformation to cancer
  38. 4 responses by p53
    • 1) cell cycle arrest¬†
    • 2) DNA repair
    • 3) block of angiogenesis
    • 4) apoptosis
  39. proteins which promote the cell cycle (most found in G1)
  40. what cyclins bind to
    CDKs (cyclin dependent kinases)
  41. most important CDK complex inhbitor
    Rb (retinoblastoma gene)
  42. what all regulators of G1 are focused on activating/repressing
  43. when the first phosphate gets put on Rb, the cell has entered ___.
  44. Rb at the end of mitosis
    completely dephosphorylated
  45. what CDK complexes are focused on
    phosphorylated Rb
  46. CDK complex that begins the process of Rb phosphorylation
  47. CDK complex that adds multiple phosphates to Rb
  48. when the cell cycle can no longer be shut down by an external signal
    once Rb becomes hyperphosphorylated and the restriction point has passed
  49. E2F (4)
    • 1) transcription factors
    • 2) sequestered by Rb in early G1
    • 3) released by Rb when hyperphosphorylated
    • 4) promote transcription of genes which will drive cell to S phase
  50. gatekeeper that keeps cells from entering cell cycle by sequestering TF's needed to transcribe essential cell cycle proteins
  51. external growth inhibitory factor
  52. what is the cell cycle driven by?
    transcription factors of the E2F family
  53. tumors that reach a certain size and then stop
    benign tumors
  54. tumors that invade vascular tissue and enter the blood
    metastasized tumors
  55. for many cancers, what does the risk come mostly from?