How Do Mutated Tumor Suppressor Genes Affect the Cell Cycle

The cell cycle is a series of events occur inside a cell, ultimately leading to its division into two daughter cells. The progress of the cell cycle is monitored and regulated by cell cycle checkpoints (Cps). The three most critical checkpoints are G₁ checkpoint, G₂checkpoint, and mitotic checkpoint. Tumor suppressor genes (TSGs) and proto-oncogenes are two types of genes involved in the regulation of the cell cycle. Tumor suppressor genes produce proteins that negatively regulate the cell cycle while proto-oncogenes positively-regulate the cell cycle.

Key Areas Covered

1. What are Tumor Suppressor Genes
– Definition, Function, Types
2. How Do Mutated Tumor Suppressor Genes Affect the Cell Cycle
– Role of Tumor Suppressor Genes in Cell Cycle

Key Terms: Cell Cycle, DNA Damage, Tumor Suppressor Genes, Uncontrolled Cell Proliferation

What are Tumor Suppressor Genes

Tumor suppressor genes refer to any class of genes that inhibit unrestrained cell division and cause malignant cell proliferation upon activation by a mutation. Hence, the main function of tumor suppressor genes is to slow down the cell division. In addition, tumor suppressor genes are involved in the repair of DNA damages or inducing programmed cell death known as apoptosis. Some tumor suppressor genes and their functions are shown in table 1.

Tumor Suppressor Genes

Tumor Suppressor Gene	Function	Type of Tumors
TP53	Cell cycle regulation, apoptosis	Brain tumors, leukemia, breast cancer, sarcomas
RB1	Cell cycle regulation	Retinoblastoma, osteogenic sarcoma
WT1	Regulation of transcription	Pediatric kidney cancer, most common form of childhood solid tumor
NF1	Catalysis of RAS activation	Neurofibromas, sarcomas, gliomas
NF2	Linkage of the cell membrane to actin cytoskeleton	Schwann cell tumors, astrocytomas, meningiomas, ependymomas
APC	Signalling through adhesion molecules to the nucleus	Colon cancer
BRC1 and BRC2	Transcription regulation and DNA repair	Breast and ovarian cancer

How Do Mutated Tumor Suppressor Genes Affect the Cell Cycle

The collective function of most well-understood tumor suppressor genes such as p53, Rb, and p21 is to inhibit the progression of cell cycle until certain events are completed. Therefore, the function of the tumor suppressor genes is like that of the brakes in a vehicle. The mutated form of tumor suppressor genes leads to the formation of malignant cells that possess uncontrolled cell proliferation.

The p53 gene plays a major role in the G₁ checkpoint when the cell enters into the S phase from G₁ phase. Hence, the mutated p53 gene may no longer halt the cell cycle at the G₁ checkpoint. The damaged DNA may also remain unrepaired. If the p53 gene is functional, the cells with damaged DNA may be subject to apoptosis. The function of both normal and mutated p53 gene are shown in figure 1.

How Do Mutated Tumor Suppressor Genes Affect the Cell Cycle_Figure 1

Figure 1: Normal and Mutated p53

The mutated p53 is also unable to trigger the production of p21 proteins. Adequate p21 levels are required for the effective blockage of CDK activation. The CDKs (cyclin-dependent kinases) are the delayed response genes of the G1 phase. Ultimately, the daughter cells may also have mutated p53 genes. These non-functional tumor suppressor genes cause uncontrolled cell proliferation, bringing the daughter cell population into a malignant stage. Generally, mutated p53 genes cause more than one-half of the cancers. The first identified tumor suppressor gene in humans is the Rb and it causes tumors in the eye called retinoblastoma.

Conclusion

Tumor suppressor genes are a class of genes that produce proteins, negatively-regulating the cell cycle. Since the main function of tumor suppressor genes is to control the cell cycle and repair DNA damages, the mutated forms of tumor suppressor genes cause uncontrolled cell proliferation.

Reference:

1.“Tumor Suppressor Genes and Activities.” Tumor Suppressors, Available here.
2.Velez, Ana Maria Abreu, and Michael S. Howard. “Tumor-Suppressor Genes, Cell Cycle Regulatory Checkpoints, and the Skin.” North American Journal of Medical Sciences, Medknow Publications & Media Pvt Ltd, May 2015, Available here.