What are tumor-suppressor genes? |

Discovery of Tumor-Suppressor Genes

The existence of genes playing critical roles in cell cycle regulation by inhibiting cell division was predicted by several lines of evidence. In vitro studies involving the fusion of normal and cancer cell lines were observed to result in suppression of the malignant phenotype, suggesting normal cells contained inhibitors with the ability to reprogram the abnormal growth behavior of the cancer cell lines. In addition, back in 1971, studies by Alfred Knudsen on inherited and noninherited forms of retinoblastoma, a childhood cancer associated with tumor formation in the eye, suggested the inactivation of recessive genes as a consequence of mutation, resulted in the loss of function of inhibitory gene products critical to cell division control. With the advent of molecular methods of genetic analysis, the gene whose inactivation is
responsible for retinoblastoma was identified and designated Rb.

Additional tumor-suppressor genes were identified by studies of DNA tumor viruses whose cancer-causing properties were found to result, in part, from the ability of specific viral gene products to inactivate host cell inhibitory gene products involved in cell cycle regulation. By inactivating these host cell proteins, the tumor virus removes the constraints on viral and cellular proliferation. The most important cellular gene product to be identified in this way is the p53 protein, named after its molecular weight. Genetic studies of human malignancies have implicated mutations in the p53
gene in up to 75 percent of tumors of diverse tissue origin, including an inherited disorder called Li-Fraumeni syndrome, which is associated with a higher risk for developing sarcomas, brain tumors, adrenal gland cancers, and leukemias. In addition, studies of other rare inherited malignancies have led to the identification of about thirty recessive tumor-suppressor genes whose inactivation contributes to oncogenic or cancer-causing cell proliferation. The accompanying table provides examples of the chromosomal locations for several tumor-suppressor genes. Included in the list are the BRCA1
and BRCA2 genes in breast cancer, the NF1 gene in neurofibromatosis, the p16 gene in melanoma, and the APC gene in colorectal carcinoma. Each of these genes has also been implicated in nonhereditary cancers. Three types of tumor-suppressor genes are generally recognized: genes controlling cell division, DNA repair, and cell death.

The Properties of Tumor-Suppressor Genes

Molecular analyses of the genetic and biochemical properties of tumor-suppressor genes have suggested some of these gene products play critical but distinct roles in regulating processes involved in cellular division and proliferation. The Rb gene product represents a prototype tumor-suppressor gene of this type. The Rb gene product normally blocks progression of the cell cycle and cell division by binding to transcription factors in its active form. In order for cell division to occur in response to growth factor stimulation, elements of the signal cascade inactivate Rb-mediated inhibition by a mechanism involving the addition of phosphate to the molecule, a reaction called phosphorylation. In cancer, loss of Rb function results as a consequence of mutation which removes the brakes on this form of normal inhibitory control; the cell division machinery proceeds without appropriate initiation by growth factors or other stimuli.

Like the Rb tumor-suppressor gene, most tumor-suppressor genes become active due to a loss of heterozygosity (LOH). Since chromosomes (and the genes residing within the chromosomes) are paired, a mutation in one gene of the pair is called heterozygosity. For Rb, a single gene mutation (the heterozygous condition for the trait encoded by the gene pair) is inherited as a recessive condition where no cancer results (since the infant has one normal gene and one mutated Rb gene). During development however, a random mutation can occur in the normal Rb gene. As soon as the second Rb gene mutates in a single cell, cancer can begin.

Tumor-suppressor genes are also found among the genes specifically involved in DNA repair. Whenever a cell divides the DNA must be duplicated, and errors in the duplication process must be repaired in order for the new cell to function properly. The protein products of DNA repair gene errors in duplicated DNA by proofreading the DNA sequence; however, if the DNA repair genes are mutated, errors will slip by and these mutations can create proteins which may activate oncogenes, or the mutations may create abnormal, mutated tumor-suppressor genes. For example, when DNA repair genes fail to repair DNA errors, some endometrial cancers and hereditary nonpolyposis colon cancer (HNPCC) can result (about 5 percent of all colon cancers).

If the cell’s DNA is damaged beyond repair by the DNA repair proteins, then the p53 tumor-suppressor gene is among the family of genes responsible for destroying the cell by causing cell death (also called “cell suicide” or “programmed cell death” or “apoptosis”). The p53 tumor-suppressor gene product is a DNA-binding protein with the ability to regulate the expression of other genes in response to genetic damage or other abnormal events occurring during cell cycle progression. In response to p53 activation, the cell will normally arrest the process of cell division (by indirectly blocking Rb inactivation). This cell cycle arrest may allow time for the cell machinery to repair genetic damage before proceeding further along the cell cycle; alternatively, if the damage is too great, the p53 gene product may initiate a process of apoptosis. The loss of p53 activity in the cell as a consequence of mutation results in genetic destabilization and the failure of cell death mechanisms to eliminate damaged cells from the body; both events appear to be critical to late-stage oncogenic mechanisms. Mutations of the p53 gene may be inherited (as in the Li-Fraumeni syndrome, LFS); however, mutations in p53 are also routinely found in many sporadic (noninherited) cancers (including lung, colon, breast, and other cancer types).

Impact and Applications

The discovery of tumor-suppressor genes has revealed the existence of inhibitory mechanisms critical to the regulation of cellular proliferation. Mutations that destroy the functional activities of these gene products cause the loss of growth control characteristic of cancer cells. Taken together, research on the patterns of oncogene activation and the loss of tumor-suppressor gene function in many types of human malignancy suggest a general model of oncogenesis. Molecular analyses of many tumors show multiple genetic alterations involving both oncogenes and tumor-suppressor genes, suggesting that oncogenesis (development of cancer) requires unregulated stimulation of cellular proliferation pathways along with a loss of inhibitory activities that operate at cell cycle checkpoints.

Some tumor-suppressor gene mutations are inherited and, in rare cases, testing for these gene mutations (which have been found often enough in the general population, like BRCA 1 and BRCA 2) may be helpful to determine which people are at higher risk for certain cancers. Genetic testing for families at risk requires careful screening and counseling and might allow surgical intervention, lifestyle changes, or more frequent cancer screening steps to minimize the individual’s familial cancer risk.

Genetic tests for oncogenes and tumor-suppressor genes have become commonplace in cancer diagnosis and treatment. Some genetic tests have been shown to help diagnose the type of cancer, guide cancer treatment, predict survival for patients with cancer, and sometimes to produce novel therapies for cancer patients.

With respect to clinical applications, restoration of p53 tumor-suppressor gene function by gene therapy appears to result in tumor regression in some experimental systems; however, much more work needs to be done in this area to achieve clinical relevance. More important, research on the mechanism of action of standard chemotherapeutic drugs suggests that cytotoxicity may be caused by p53-induced cell death; the absence of functional p53 in many tumors may account for their resistance to chemotherapy. Promising research is investigating new ways to elicit cell death in tumor cells lacking functional p53 gene product in response to chemotherapy. The clinical significance of activating these p53-independent cell death mechanisms may be extraordinary.

Key Terms




cell cycle


:

a highly regulated series of events critical to the initiation and control of cell division processes





oncogenes


:

mutated or improperly expressed genes known to cause cancer; the normal form of an oncogene is called a proto-oncogene, which is usually involved in regulating the cell cycle; however, activating or “turning on” the proto-oncogene (through mutation or improper expression) results in cancer




p53 gene

:

a tumor-suppressor gene implicated in many types of cancer




Rb gene

:

a tumor-suppressor gene, when inactivated, is associated with several cancers including the formation of a rare and lethal eye tumor (retinoblastoma) in infants





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