thumb|186x186px|The [[cell cycle. Many tumor suppressors work to regulate the cycle at specific checkpoints in order to prevent damaged cells from replicating.]]

A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.

TSGs can be grouped into the following categories: caretaker genes, gatekeeper genes, and more recently landscaper genes. Caretaker genes ensure stability of the genome via DNA repair and subsequently when mutated allow mutations to accumulate. Meanwhile, gatekeeper genes directly regulate cell growth by either inhibiting cell cycle progression or inducing apoptosis. The classification schemes are evolving as medical advances are being made from fields including molecular biology, genetics, and epigenetics.

History

The discovery of oncogenes and their ability to deregulate cellular processes related to cell proliferation and development appeared first in the literature as opposed to the idea of tumor suppressor genes. However, the idea of genetic mutation leading to increased tumor growth gave way to another possible genetic idea of genes playing a role in decreasing cellular growth and development of cells. This idea was not solidified until experiments by Henry Harris were conducted with somatic cell hybridization in 1969.

Within Harris's experiments, tumor cells were fused with normal somatic cells to make hybrid cells. Each cell had chromosomes from both parents and upon growth, a majority of these hybrid cells did not have the capability of developing tumors within animals. He observed that 40% of U.S cases were caused by a mutation in the germ-line. However, affected parents could have children without the disease, but the unaffected children became parents of children with retinoblastoma. This indicates that one could inherit a mutated germ-line but not display the disease. Knudson observed that the age of onset of retinoblastoma followed 2nd order kinetics, implying that two independent genetic events were necessary. He recognized that this was consistent with a recessive mutation involving a single gene, but requiring bi-allelic mutation. Hereditary cases involve an inherited mutation and a single mutation in the normal allele. Other tumor-suppressor genes that do not follow the two-hit rule are those that exhibit haploinsufficiency, including PTCH in medulloblastoma and NF1 in neurofibroma. Another example is p27, a cell-cycle inhibitor, that when one allele is mutated causes increased carcinogen susceptibility.

Functions

The proteins encoded by most tumor suppressor genes inhibit cell proliferation or survival. Inactivation of tumor suppressor genes therefore leads to tumor development by eliminating negative regulatory proteins. In most cases, tumor suppressor proteins inhibit the same cell regulatory pathways that are stimulated by the products of oncogenes. While tumor suppressor genes have the same main function, they have various mechanisms of action, that their transcribed products perform, which include the following:

  1. Intracellular proteins, that control gene expression of a specific stage of the cell cycle. If these genes are not expressed, the cell cycle does not continue, effectively inhibiting cell division. (e.g., pRB and p16)
  2. Receptors or signal transducers for secreted hormones or developmental signals that inhibit cell proliferation (e.g., transforming growth factor (TGF)-β and adenomatous polyposis coli (APC)).
  3. Checkpoint-control proteins that trigger cell cycle arrest in response to DNA damage or chromosomal defects (e.g., breast cancer type 1 susceptibility protein (BRCA1), p16, and p14).
  4. Proteins that induce apoptosis. If damage cannot be repaired, the cell initiates programmed cell death to remove the threat it poses to the organism as a whole. (e.g., p53).
  5. Cell adhesion. Some proteins involved in cell adhesion prevent tumor cells from dispersing, block loss of contact inhibition, and inhibit metastasis. These proteins are known as metastasis suppressors. (e.g., CADM1)
  6. Proteins involved in repairing mistakes in DNA. Caretaker genes encode proteins that function in repairing mutations in the genome, preventing cells from replicating with mutations. Furthermore, increased mutation rate from decreased DNA repair leads to increased inactivation of other tumor suppressors and activation of oncogenes. (e.g., p53 and DNA mismatch repair protein 2 (MSH2)).
  7. Certain genes can also act as tumor suppressors and oncogenes. Dubbed Proto-oncogenes with Tumor suppressor function, these genes act as "double agents" that both positively and negatively regulate transcription. (e.g., NOTCH receptors, TP53 and FAS).

Epigenetic influences

Expression of genes, including tumor suppressors, can be altered through biochemical alterations known as DNA methylation. Methylation is an example of epigenetic modifications, which commonly regulate expression in mammalian genes. The addition of a methyl group to either histone tails or directly on DNA causes the nucleosome to pack tightly together restricting the transcription of any genes in this region. This process not only has the capabilities to inhibit gene expression, it can also increase the chance of mutations. Stephen Baylin observed that if promoter regions experience a phenomenon known as hypermethylation, it could result in later transcriptional errors, tumor suppressor gene silencing, protein misfolding, and eventually cancer growth. Baylin et al. found methylation inhibitors known as azacitidine and decitabine. These compounds can actually help prevent cancer growth by inducing re-expression of previously silenced genes, arresting the cell cycle of the tumor cell and forcing it into apoptosis.

There are further clinical trials under current investigation regarding treatments for hypermethylation as well as alternate tumor suppression therapies that include prevention of tissue hyperplasia, tumor development, or metastatic spread of tumors. The team working with Wajed have investigated neoplastic tissue methylation in order to one day identify early treatment options for gene modification that can silence the tumor suppressor gene. In this method, vectors from viruses are used. The two most commonly used vectors are adenoviral vectors and adeno-associated vectors. In vitro genetic manipulation of these types of vectors is easy and in vivo application is relatively safe compared to other vectors. Before the vectors are inserted into the tumors of the host, they are prepared by having the parts of their genome that control replication either mutated or deleted. This makes them safer for insertion. Then, the desired genetic material is inserted and ligated to the vector.

Non-viral methods

The non-viral method of transferring genetic material is used less often than the viral method.

  • Retinoblastoma protein (pRb). pRb was the first tumor-suppressor protein discovered in human retinoblastoma; however, recent evidence has also implicated pRb as a tumor-survival factor. RB1 gene is a gatekeeper gene that blocks cell proliferation, regulates cell division and cell death. This prevents the cell from replicating its DNA if there is damage.
  • p53. TP53, a caretaker gene, encodes the protein p53, which is nicknamed "the guardian of the genome". p53 has many different functions in the cell including DNA repair, inducing apoptosis, transcription, and regulating the cell cycle. Mutated p53 is involved in many human cancers, of the 6.5 million cancer diagnoses each year about 37% are connected to p53 mutations. The main function is involved in maintaining the composition of the mitochondria membrane, and preventing cytochrome c release into the cytosol.
  • SWI/SNF. SWI/SNF is a chromatin remodeling complex, which is lost in about 20% of tumors. The complex consists of 10-15 subunits encoded by 20 different genes.

See also

  • Anticancer gene
  • Metastasis suppressor
  • Adenomatosis polyposis coli
  • Oncogene
  • Cancer
  • DNA repair
  • Signal transduction
  • Von Hippel Lindau Binding protein 1
  • BRCA1
  • p53

References

  • TCF21 gene discovery at Ohio State University
  • Drosophila Oncogenes and Tumor Suppressors - The Interactive Fly
  • Tumor Suppressor Gene Database, published in 2012