3. When patients are biopsied for cancer, expression of tumor suppressors genes

Question

3. When patients are biopsied for cancer, expression of tumor suppressors genes (proteins that protects cells from cancer) are usually not expressed, or mutated, thus nonfunctional. As a pathologist, you discover that a biopsy from your colon cancer patient has the following characteristics: a. mRNA expression for tumor suppressors are present, but you can't detect any functional protein b. protein expression levels for ubiquitin and the 26S proteasome are extremely high, much higher than they would be for a normal, healthy adult Give an explanation that would correlate high ubiquitin and 26S expression and low tumor suppressor protein in this colon cancer patient.

Explanation / Answer

Intracellular protein degradation occurs in the cell by the ubiquitin proteosome pathway. Proteins involved in cell cycle, apoptosis, transcription, DNA repair, this pathway degrades protein quality control and antigen presentation. There are three enzymes involved in this multistep process- E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme) and E3 (ubiquitin ligase). A thiol ester bond between E1 and ubiquitin is fits formed in presence of ATP. The activated ubiquitin moiety is transferred to the active site of E2 enzyme. The ubiquitin is then shuttled either directly or in concert with an E3 enzyme to lysine present in the target protein. As more and more ubiquitin is transferred to form a polyubiquitin chain. This polyubiquitin chain is a signal for degradation by 26S proteosome.

High proteosome activity is observed in colon cancer to degrade immature and irregular proteins that are produced by the cancer cells. Mutations that inactive the APC (adenomatous polyposis coli) gene are in most human colon tumors. APC is a tumor suppressor that controls the levels of beta catenin in the colon cells. It is a part of the complex that phosphorylates beta catenin and targets it for degradation. When APC is mutated, the beta catenin is active, enters the nucleus, and activates transcription of oncogenes such as c-myc and cyclins. Mutant APC is irregular and has to be targeted for degradation by ubiquitin proteosome pathway. Hence, ubiquitin and 26S proteosome levels increase in colon cancer cells in order to degrade the mutant APC proteins produced.

Similarly, another tumor suppressor protein p53 are decreased in colon cancer. MDM2 (Murine Double Minute2) protein is a E3 ubiquitin ligase protein that phosphorylates p53 and targets it for degradation. MDM2 levels are elevated in colon cancers. Thus, levels of ubiquitin and 26S proteosome proteins increase, even when tumor suppressor gene proteins decrease. The mRNA for these tumor suppressor genes are however, produced.

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