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The Proteasome

Protein degradation is as essential to the cell as protein synthesis. For example, There are two major intracellular devices in which damaged or unneeded proteins are broken down:

Lysosomes deal primarily with

Link to a discussion of lysosomes.

Proteasomes deal primarily with endogenous proteins; that is, proteins that were synthesized within the cell such as:

Structure of the Proteasome

The Core Particle (CP)

The Regulatory Particle (RP)


The Process

Proteins destined for destruction

Bortezomib (Velcade®)

On 13 May 2003, the U.S. Food and Drug Administration (FDA) approved a drug called bortezomib (Velcade®) (formerly known as LDP-341) to treat patients with multiple myeloma, a cancer of plasma cells.

The drug blocks the proteolytic action of the proteasome.
  • The failure to degrade IκB blocks the signaling action of the transcription factor NF-κB. [Discussion] Dozens of genes needed for proliferation and adhesion of myeloma cells are turned off.
  • The failure to degrade cyclins inhibits completion of the cell cycle and hence the mitotic proliferation of the cancerous cells.
  • The drug seems to work especially well when used with conventional chemotherapy drugs probably by inhibiting the ability of the cancer cell to protect itself against the damage "chemo" causes.
  • Inhibition of Bcl-2 leads to death of the cell by apoptosis.
  • Angiogenesis and metastasis are also inhibited.
The drug is given intermittently, and its action is reversible. Cancer cells are killed while normal cells are spared.

Antigen Processing by Proteasomes

In mammals, activation of the immune system
Link to a discussion of antigen presentation in the class I pathway.
It is probably no coincidence that the genes encoding
  • the three substitute core particle subunits
  • TAP
  • all the MHC molecules
are clustered together on the same chromosome (#6 in humans).

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19 April 2013