The TP53 gene encodes the p53 protein. This 393-amino acid protein is a transcri

Question

The TP53 gene encodes the p53 protein. This 393-amino acid protein is a transcription factor that is regulated by phosphorylation and by its interaction with another phosphoprotein, the negative regulator Mdm2. In a normal cell, both proteins are unphosphorylated, which allows them to bind together. Mdm2 stimulates degradation of p53, and, as a result, the amount of p53 in the cell is low. When DNA damage occurs, p53 initiates a cascade of events leading to arrest in G1. DNA damage results in phosphorylation of both p53 and Mdm2 on the domains where they normally interact. Therefore, a p53-Mdm2 complex cannot form and p53 degradation is not promoted. P53 accumulates. Functioning as a transcription factor, p53 turns on transcription of DNA repair genes and of WAF1, which encodes a protein called p21. The p21 protein binds to the G1 to S checkpoint Cdk4-cyclin D complexes and inhibits their activity. As a result, pRB in the pRB complex does not become phosphorylated, thereby keeping e2F inhibited. Entry into S phase is blocked and the cell arrests in G1.
The p21 protein can also bind to other checkpoint Cdk-cyclin complexes and inhibit their activity, thereby blocking the cell cycle at any stage. The example here focuses on the retinoblastoma protein and the G1 to S checkpoint.

a. Is the TP53 gene considered a proto-oncogene or a tumor suppressor gene? Explain your answer.

b. Why is the WAF1 gene considered a tumor suppressor gene? Explain your answer

c. Why are mutations in the WAF1 gene and other tumor suppressor genes considered recessive mutations?

d. How might a point mutation create an inactive form of p53?

Explanation / Answer

a) important tumor suppressor is the p53 tumor-suppressor protein encoded by the TP53 gene. b) is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer. As such, p53 has been described as "the guardian of the genome", the "guardian angel gene", and the "master watchman", referring to its role in conserving stability by preventing genome mutation. The name p53 is in reference to its apparent molecular mass: It runs as a 53-kilodalton (kDa) protein on SDS-PAGE. But, based on calculations from its amino acid residues, p53's mass is actually only 43.7 kDa. This difference is due to the high number of proline residues in the protein, which slow its migration on SDS-PAGE, thus making it appear heavier than it actually is. This effect is observed with p53 from a variety of species, including humans, rodents, frogs, and fish. In healthy humans, the p53 protein is continually produced and degraded in the cell. The degradation of the p53 protein is, as mentioned, associated with MDM2 binding. In a negative feedback loop, MDM2 is itself induced by the p53 protein. However, mutant p53 proteins often do not induce MDM2, and are thus able to accumulate at very high concentrations. Worse, mutant p53 protein itself can inhibit normal p53 protein levels. Tumor suppressors inhibit cell growth, promote differentiation, or stimulate apoptosis. They also suppress genomic instability, allowing cells to sense or repair DNA damage. In contrast to the gain-of-function mutations that activate proto-oncogenes, oncogenic mutations in tumor suppressor genes generally delete or inactivate the gene (loss of function). In most cases, both gene copies must be inactivated before loss-of-function is obvious. Thus, oncogenic mutations in tumor suppressor genes tend to be recessive. Tumor suppressors include growth inhibitors and their receptors and signal transducers, transcription factors, proapoptotic proteins, and proteins that sense or repair DNA damage. Inactivating mutations are often chromosome aberrations that delete large segments of DNA. However, more subtle mutations (for example, point mutations) can also inactivate tumor suppressors. The most widely studied, and possibly most important, tumor suppressor genes are RB and TP53, which encode the pRB and p53 proteins. These proteins are at the heart of two major tumor-suppressor pathways, each comprised of many interacting proteins. They are critical for the control of cellular senescence and are mutated in over 80 percent of human cancers.

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