Biology 207Spring 2004

Biology of Cancer

Lecture 11: Cell Signaling

Reading: King Chap. 11

Reference:Lodish et al. Molecular Cell Biology. Fifth edition. Chap. 13 and 14.

Outline:

1. Proto-oncogenes and cell signaling pathways

a. growth factors

b. growth factor receptors

c. intracellular signaling

d. transcriptional activation

Lecture:

1. Pathways of cell signaling

  • Many oncogenes turn out to encode cell signaling molecules. When proto-oncogenes are mutated, altered proteins are produced or the proteins are overexpressed.
  • The normal cellular genes may encode growth factors, receptors, or molecules involved in cell signaling.

a. Growth factors--Small molecules, often peptides (short proteins) that stimulate cell growth and division.

Example: PDGF=platelet derived growth factor.

  • Oncogene name: sis.
  • Under normal conditions stimulates cell growth.
  • In cancer, growth factor is received by wrong type of cell or too much is received.

b. Growth factor receptors--Proteins on the surface of cells that bind to specific growth factors (ligands) and transmit signals to the cell.

Examples:

  • src, associated with sarcomas
  • erbB-2 (epidermal growth factor receptor) associated with ovarian cancer
  • her-2/neu receptor, associated with aggressive breast cancer
  • Receive signals from extracellular environment and convert this to an intracellular signal.
  • Under normal conditions, the receptor receives signals, passes them on, then waits.
  • In cancer, you may have too many receptors or receptors that have a lower threshold for action.
  • Mutations in the sequence encoding the receptor may leave it effectively stuck in the ON position.

Many receptors such as src are kinases. They transfer phosphates to other molecules such as proteins.

inactive protein +ATP  active protein-PO4 + ADP

c. Intracellular signaling.

Signal transduction--The processes a cell uses to transmit signals from the outside to a location in the cell where action can be taken.

  • Signaling pathways involve interactions of various molecules (often proteins) in an ordered sequence. Think of as a "bucket brigade".
  • Pathways can branch in different directions and different pathways can culminate in the same molecule.

Example:

  • ras (important in many cancers, including colon cancer and bladder cancer)
  • a guanine nucleotide binding protein
  • acts as a molecular switch
  • Under normal conditions, the switch goes on and off depending on the binding of GTP (active) or GDP (inactive).
  • In cancer, mutant ras contains a single amino acid substitution that leaves ras in the active (GTP bound) state. ALWAYS ON!

Ras receives information from receptor tyrosine kinases indirectly via adaptor proteins.

In a signal transduction pathway, upstream signals pass on molecules to other downstream molecules.

Growth factor + growth factor receptorinternal signal via tyrosine kinase of receptor adaptor proteinsras rafMEKMap kinaseactivated transcription factor (SRF)

Many of the proteins in signal transduction pathways have turned out to be oncogenic when mutated or overexpressed, for example ras and raf.

Note: You need not learn an entire signal transduction pathway--whichever one you learn will be out of date in months!

d. Transcription factors--Proteins that promote (or repress) the transcription of particular genes.

  • Many of the cell signaling pathways end by activating transcription factors that regulate particular genes involved in growth.
  • Transcription factors usually help RNA polymerase II to bind to the promoter region of a gene and activate transcription.

Examples: c-myc (associated with Burkitt's lymphoma)

fos

jun

  • Under normal conditions, these transcription factors only activate transcription when they are phosphorylated or receive some other type of signal.
  • In cancer, the transcription factors bind to DNA and activate genes without having received a signal. They become stuck in the ON position.

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