Tumour Suppressor Genes

INTRODUCTION

We know that cancer is a result of errors in cell cycle caused by the activation of certain oncogenes such as RAS and MYC. Well, as it turns out our body has a mechanism to prevent any abnormal cells from progressing through the cell cycle. So, an abnormal cell can only bypass the cell cycle when the tumour suppressor genes are inactivated. There can be some inherited abnormalities in tumour suppressor genes causing a certain type of cancer to run in families, usually, these abnormalities are acquired and not inherited. There is an increased rate of mutations in the DNA in the presence of carcinogens and if these tumour suppressor genes get mutated their effectiveness reduces. As many as 50% of all human tumours contain a mutated p53 gene.

One of the major tumour suppressor genes is tp53 which codes for the protein p53. It is described as “the guardian of the genome” because it conserves the stability of genome by preventing gene mutations. In humans, this gene is present on the seventeenth chromosome and performs the following functions:

1) Plays a key role in the regulation of the cell cycle as it can arrest mitosis if there are significant mutations.

2) Involved in the repair of damaged DNA.

3) If the DNA is beyond repair, it can trigger apoptosis which is programmed cell death.

WORKING

p53 proteins cause the cell cycle to arrest at the G1 phase. It does by acting as a transcriptional regulator on the WAF1 gene which causes the production p21 proteins. Now, p21 block CDK4/Cyclin D complex thus bringing the cell cycle to halt.

By arresting cell cycle at G1 phase, p53 makes time for DNA repair to take place by inducing DNA repair genes. If the DNA is repaired, p53 proteins will degenerate and cell cycle will continue. If the cell is beyond repair cell apoptosis will take place.

REGULATION OF p53 PROTEIN

p53 regulates another gene called the Mdm2 gene resulting in the production of Mdm2 proteins. These bind with p53 proteins and form the p53-Mdm2 complex. Now, this complex degrades resulting in the formation of degraded p53 as seen in (Fig 4.3).

If the DNA is damaged p53 protein gets phosphorylated and prevents the action of Mdm2 protein causing the increase in the concentration of p53 proteins (as they are not getting degraded) as seen in (Fig 4.4).

If tp53 is inactive or mutated the cell with damaged DNA would pass the G1 checkpoint and would continue to grow and proliferate forming a malignant tumour.

BIBLIOGRAPHY

Primary Information of p53 Gene, www.bioinformatics.org/p53/introduction.html.

National Center for Biotechnology Information (US). “The p53 Tumor Suppressor Protein.” Genes and Disease [Internet]., U.S. National Library of Medicine, 1 Jan. 1998, www.ncbi.nlm.nih.gov/books/NBK22268/.

“Oncogenes and Tumor Suppressor Genes.” American Cancer Society, www.cancer.org/cancer/cancer-causes/genetics/genes-and-cancer/oncogenes-tumor-suppressor-genes.html.

Sionov, Ronit Vogt. “The Regulation of p53 Growth Suppression.” Madame Curie Bioscience Database [Internet]., U.S. National Library of Medicine, 1 Jan. 1970, www.ncbi.nlm.nih.gov/books/NBK6412/.

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