Tumor suppressor gene

A tumor suppressor gene (TSG), or anti-oncogene, is a

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.^[3] Meanwhile, gatekeeper genes directly regulate cell growth by either inhibiting cell cycle progression or inducing apoptosis.^[3] Lastly landscaper genes regulate growth by contributing to the surrounding environment, when mutated can cause an environment that promotes unregulated proliferation.^[4] The classification schemes are evolving as medical advances are being made from fields including molecular biology, genetics, and epigenetics.

History

The discovery of

dominant.

Proposed by A.G. Knudson for cases of retinoblastoma.^[7] 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.^[8] 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.^[8] Non-hereditary retinoblastoma involves two mutations, one on each allele.^[8] Knudson also noted that hereditary cases often developed bilateral tumors and would develop them earlier in life, compared to non-hereditary cases where individuals were only affected by a single tumor.^[8]

There are exceptions to the two-hit rule for tumor suppressors, such as certain mutations in the

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)^[13]
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)).^[14]
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).^[15]
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).^[16]
5. CADM1)^[17][18]
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.^[19] (e.g., p53 and DNA mismatch repair protein 2 (MSH2)).^[20]
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).^[21]

Epigenetic influences

Expression of genes, including tumor suppressors, can be altered through biochemical alterations known as DNA methylation.^[22] 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.^[23]

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.^[24] 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.^[25] In addition to DNA methylation, other epigenetic modifications like histone deacetylation or chromatin-binding proteins can prevent DNA polymerase from effectively transcribing desired sequences, such as ones containing tumor suppressor genes.

Clinical significance

Gene therapy is used to reinstate the function of a mutated or deleted gene type. When tumor suppressor genes are altered in a way that results in less or no expression, several severe problems can arise for the host. This is why tumor suppressor genes have commonly been studied and used for gene therapy. The two main approaches used currently to introduce genetic material into cells are viral and non-viral delivery methods.^[25]

Viral methods

The viral method of transferring genetic material harnesses the power of

The viral and non-viral gene therapies mentioned above are commonly used but each has some limitations which must be considered. The most important limitation these methods have is the efficacy at which the adenoviral and adeno-associated vectors, naked plasmids, or liposome-coated plasmids are taken in by the host’s tumor cells. If proper uptake by the host’s tumor cells is not achieved, re-insertion introduces problems such as the host’s immune system recognizing these vectors or plasmids and destroying them which impairs the overall effectiveness of the gene therapy treatment further.[28]

Examples

^[25]

• 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.^[8] Specifically pRb prevents the cell cycle progression from G1 phase into the S phase by binding to E2F and repressing the necessary gene transcription.^[29] This prevents the cell from replicating its DNA if there is damage.
• p53. TP53, a caretaker gene, encodes the protein
  Li-Fraumeni syndrome
  (LFS), which increases the risk of developing various types of cancers.
• BCL2. BCL2 is a family of proteins that are involved in either inducing or inhibiting apoptosis.^[31] The main function is involved in maintaining the composition of the mitochondria membrane, and preventing cytochrome c release into the cytosol.^[31] When cytochrome c is released from the mitochondria it starts a signaling cascade to begin apoptosis.^[32]
• SWI/SNF. SWI/SNF is a chromatin remodeling complex, which is lost in about 20% of tumors.^[33] The complex consists of 10-15 subunits encoded by 20 different genes.^[33] Mutations in the individual complexes can lead to misfolding, which compromises the ability of the complex to work together as a whole. SWI/SNF has the ability move nucleosomes, which condenses DNA, allowing for transcription or block transcription from occurring for certain genes.^[33] Mutating this ability could cause genes to be turned on or off at the wrong times.

As the cost of DNA sequencing continues to diminish, more cancers can be sequenced. This allows for the discovery of novel tumor suppressors and can give insight on how to treat and cure different cancers in the future. Other examples of tumor suppressors include

See also

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

References