Editing Tumor suppressor gene

{{Short description|Gene that inhibits expression of the tumorigenic phenotype}}
[[File:Cell Cycle 3-3.svg|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 (biology)|cell]] during cell division and replication.<ref>{{Cite web|url=https://www.cancer.org/cancer/cancer-causes/genetics/genes-and-cancer/oncogenes-tumor-suppressor-genes.html|title=Oncogenes and tumor suppressor genes {{!}} American Cancer Society|website=www.cancer.org|language=en|access-date=2019-09-26|archive-date=2021-03-18|archive-url=https://web.archive.org/web/20210318042535/https://www.cancer.org/cancer/cancer-causes/genetics/genes-and-cancer/oncogenes-tumor-suppressor-genes.html|url-status=dead}}</ref> If the cell grows uncontrollably, it will result in [[cancer]]. 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 mutation|loss of function]] for these genes may be even more significant in the development of human cancers, compared to the activation of [[oncogene]]s.<ref>Weinberg, Robert A (2014). "The Biology of Cancer." Garland Science, page 231.</ref>

TSGs can be grouped into the following categories: [[caretaker gene]]s, 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.<ref name=":2">{{Cite web|url=http://www.cancerindex.org/geneweb/glossdef.htm|title=Glossary of Cancer Genetics (side-frame)|website=www.cancerindex.org|access-date=2019-11-19}}</ref> Meanwhile, gatekeeper genes directly regulate cell growth by either inhibiting cell cycle progression or inducing [[apoptosis]].<ref name=":2" /> Lastly, landscaper genes regulate growth by contributing to the surrounding environment, and when mutated, can cause an environment that promotes unregulated proliferation.<ref>{{Cite web|url=http://www.cubocube.com/dashboard.php?a=347&b=428&c=1|title=Cancer Genetics - CuboCube|website=www.cubocube.com|language=en|access-date=2019-11-19|archive-date=2020-10-12|archive-url=https://web.archive.org/web/20201012025310/http://www.cubocube.com/dashboard.php?a=347&b=428&c=1|url-status=dead}}</ref> 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.<ref name=":6">{{cite journal | doi=10.1016/S0092-8674(03)01075-4 | title=Principles of Tumor Suppression | year=2004 | last1=Sherr | first1=Charles J. | journal=Cell | volume=116 | issue=2 | pages=235–246 | pmid=14744434 | s2cid=18712326 | doi-access=free }}</ref> However, the idea of genetic mutation leading to increased [[Tumor progression|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 (scientist)|Henry Harris]] were conducted with [[Somatic fusion|somatic cell hybridization]] in 1969.<ref name=":5">Cooper, G. M. (2000). Tumor Suppressor Genes. The Cell: A Molecular Approach. 2nd Edition. https://www.ncbi.nlm.nih.gov/books/NBK9894/</ref>

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.<ref name=":5" /> The suppression of [[tumorigenicity]] in these hybrid cells prompted researchers to hypothesize that [[genes]] within the normal [[somatic cell]] had inhibitory actions to stop tumor growth.<ref name=":5" /> This initial hypothesis eventually lead to the discovery of the first classic tumor suppressor gene by [[Alfred G. Knudson|Alfred Knudson]], known as the Rb gene, which codes for the [[Retinoblastoma protein|retinoblastoma tumor suppressor protein]].<ref name=":6" />

[[Alfred G. Knudson|Alfred Knudson]], a pediatrician and cancer geneticist, proposed that in order to develop [[retinoblastoma]], two [[mutation|allelic mutations]] are required to lose functional copies of both the Rb genes to lead to [[tumorigenicity]].<ref name=":5" /> Knudson observed that retinoblastoma often developed early in life for younger patients in both eyes, while in some rarer cases retinoblastoma would develop later in life and only be unilateral.<ref name=":6" /> This unique development pattern allowed Knudson and several other scientific groups in 1971 to correctly hypothesize that the early development of retinoblastoma was caused by [[Heredity|inheritance]] of one loss of function mutation to an RB [[germline|germ-line gene]] followed by a later [[De novo mutations|de novo mutation]] on its functional Rb gene [[allele]]. The more sporadic occurrence of unilateral development of retinoblastoma was hypothesized to develop much later in life due to two [[de novo mutations]] that were needed to fully lose tumor suppressor properties.<ref name=":6" /> This finding formed the basis of the two-hit hypothesis. In order to verify that the [[Mutation|loss of function]] of tumor suppressor genes causes increased [[tumorigenicity]], interstitial deletion experiments on  [[chromosome 13]]q14 were conducted to observe the effect of deleting the [[Locus (genetics)|loci]] for the Rb gene. This deletion caused increased tumor growth in retinoblastoma, suggesting that [[Mutation|loss or inactivation]] of a tumor suppressor gene can increase [[tumorigenicity]].<ref name=":5" />

==Two-hit hypothesis==
Unlike [[oncogene]]s, tumor suppressor genes generally follow the [[two-hit hypothesis]], which states both alleles that code for a particular protein must be affected before an effect is manifested.<ref name=":1" /> If only one allele for the gene is damaged, the other can still produce enough of the correct protein to retain the appropriate function. In other words, mutant tumor suppressor alleles are usually [[Dominance relationship|recessive]], whereas mutant [[oncogene]] alleles are typically [[Dominance relationship|dominant]]{{cn|date=March 2025}}.[[Image:Models of tumour suppression.svg|right|thumb|Models of tumor suppression]] [[File:Two-hit.jpg|thumb|Illustration of two-hit hypothesis]]

Proposed by [[Alfred G. Knudson|A.G. Knudson]] for cases of retinoblastoma.<ref name=":1">{{cite journal | vauthors = Knudson AG | title = Mutation and cancer: statistical study of retinoblastoma | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 68 | issue = 4 | pages = 820–823 | date = April 1971 | pmid = 5279523 | pmc = 389051 | doi = 10.1073/pnas.68.4.820 | doi-access = free | bibcode = 1971PNAS...68..820K }}</ref> 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.<ref name=":0">{{Cite web|url=https://www.nature.com/scitable/topicpage/tumor-suppressor-ts-genes-and-the-two-887/|title=Tumor Suppressor (TS) Genes and the Two-Hit Hypothesis {{!}} Learn Science at Scitable|website=www.nature.com|language=en|access-date=2019-10-06}}</ref> 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 [[Rate equation#Second order reactions|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.<ref name=":0" /> Non-hereditary retinoblastoma involves two mutations, one on each allele.<ref name=":0" /> 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.<ref name=":0" />

There are exceptions to the two-hit rule for tumor suppressors, such as certain mutations in the [[p53 (protein)|p53 gene product]].  p53 mutations can function as a [[dominant negative]], meaning that a mutated p53 protein can prevent the function of the natural protein produced from the non-mutated allele.<ref>{{cite journal | vauthors = Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B | title = Suppression of human colorectal carcinoma cell growth by wild-type p53 | journal = Science | volume = 249 | issue = 4971 | pages = 912–915 | date = August 1990 | pmid = 2144057 | doi = 10.1126/science.2144057 | bibcode = 1990Sci...249..912B }}</ref> 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 (gene)|p27]], a cell-cycle inhibitor, that when one allele is mutated causes increased carcinogen susceptibility.<ref>{{cite journal | vauthors = Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ | title = The murine gene p27Kip1 is haplo-insufficient for tumour suppression | journal = Nature | volume = 396 | issue = 6707 | pages = 177–180 | date = November 1998 | pmid = 9823898 | pmc = 5395202 | doi = 10.1038/24179 | bibcode = 1998Natur.396..177F }}</ref>

==Functions==
The [[genetics|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 [[Regulator gene|regulatory proteins]]. In most cases, tumor suppressor proteins inhibit the same cell regulatory pathways that are stimulated by the products of [[oncogenes]].<ref>{{cite book | vauthors = Cooper GM | chapter = Tumor Suppressor Genes | title = The Cell: A Molecular Approach |date=2000 |edition=2nd | chapter-url= https://www.ncbi.nlm.nih.gov/books/NBK9894/ | location = Sunderland (MA) | publisher = Sinauer Associates }}</ref> While tumor suppressor genes have the same main function, they have various mechanisms of action, that their transcribed products perform, which include the following:<ref>{{cite journal | vauthors = Wang LH, Wu CF, Rajasekaran N, Shin YK | title = Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview | journal = Cellular Physiology and Biochemistry | volume = 51 | issue = 6 | pages = 2647–2693 | date = 2018 | pmid = 30562755 | doi = 10.1159/000495956 | doi-access = free }}</ref>
# 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., [[Retinoblastoma protein|pRB]] and [[p16]])<ref>{{cite journal | vauthors = Leiderman YI, Kiss S, Mukai S | title = Molecular genetics of RB1--the retinoblastoma gene | journal = Seminars in Ophthalmology | volume = 22 | issue = 4 | pages = 247–254 | date = 2007 | pmid = 18097988 | doi = 10.1080/08820530701745165 | s2cid = 42925807 }}</ref>
# Receptors or [[Signal transduction|signal transducers]] for secreted [[hormone]]s or developmental signals that inhibit cell proliferation (e.g., [[transforming growth factor]] (TGF)-β and [[adenomatous polyposis coli]] (APC)).<ref>{{cite journal | vauthors = Smith AL, Robin TP, Ford HL | title = Molecular pathways: targeting the TGF-β pathway for cancer therapy | journal = Clinical Cancer Research | volume = 18 | issue = 17 | pages = 4514–4521 | date = September 2012 | pmid = 22711703 | doi = 10.1158/1078-0432.CCR-11-3224 | doi-access = free }}</ref>
# Checkpoint-control proteins that trigger [[cell cycle]] arrest in response to [[DNA damage (naturally occurring)|DNA damage]] or chromosomal defects (e.g., [[BRCA1|breast cancer type 1 susceptibility protein]] (BRCA1), [[p16]], and [[p14arf|p14]]).<ref>{{cite journal | vauthors = Savage KI, Harkin DP | title = BRCA1, a 'complex' protein involved in the maintenance of genomic stability | journal = The FEBS Journal | volume = 282 | issue = 4 | pages = 630–646 | date = February 2015 | pmid = 25400280 | doi = 10.1111/febs.13150 | doi-access = free }}</ref>
# 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]]).<ref>{{cite journal | vauthors = Nayak SK, Panesar PS, Kumar H | title = p53-Induced apoptosis and inhibitors of p53 | journal = Current Medicinal Chemistry | volume = 16 | issue = 21 | pages = 2627–2640 | date = 2009 | pmid = 19601800 | doi = 10.2174/092986709788681976 }}</ref>
# [[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 suppressor]]s. (e.g., [[CADM1]])<ref name="pmid11058615">{{cite journal | vauthors = Yoshida BA, Sokoloff MM, Welch DR, Rinker-Schaeffer CW | title = Metastasis-suppressor genes: a review and perspective on an emerging field | journal = Journal of the National Cancer Institute | volume = 92 | issue = 21 | pages = 1717–1730 | date = November 2000 | pmid = 11058615 | doi = 10.1093/jnci/92.21.1717 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Hirohashi S, Kanai Y | title = Cell adhesion system and human cancer morphogenesis | journal = Cancer Science | volume = 94 | issue = 7 | pages = 575–581 | date = July 2003 | pmid = 12841864 | doi = 10.1111/j.1349-7006.2003.tb01485.x | s2cid = 22154824 | doi-access = free | pmc = 11160151 }}</ref>
# 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.<ref>{{cite journal | vauthors = Markowitz S | title = DNA repair defects inactivate tumor suppressor genes and induce hereditary and sporadic colon cancers | journal = Journal of Clinical Oncology | volume = 18 | issue = 21 Suppl | pages = 75S–80S | date = November 2000 | pmid = 11060332 }}</ref> (e.g., [[p53]] and [[MSH2|DNA mismatch repair protein 2]] (MSH2)).<ref>{{cite journal | vauthors = Rahman N, Scott RH | title = Cancer genes associated with phenotypes in monoallelic and biallelic mutation carriers: new lessons from old players | journal = Human Molecular Genetics | volume = 16 Spec No 1 | issue = R1 | pages = R60–R66 | date = April 2007 | pmid = 17613548 | doi = 10.1093/hmg/ddm026 | doi-access =  }}</ref>
# 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 (biology)|transcription]]. (e.g., [[Notch signaling pathway|NOTCH receptors]], [[p53|TP53]] and [[Fas receptor|FAS]]).<ref>{{cite journal | vauthors = Shen L, Shi Q, Wang W | title = Double agents: genes with both oncogenic and tumor-suppressor functions | journal = Oncogenesis | volume = 7 | issue = 3 | pages = 25 | date = March 2018 | pmid = 29540752 | pmc = 5852963 | doi = 10.1038/s41389-018-0034-x }}</ref>

== Epigenetic influences ==
Expression of genes, including tumor suppressors, can be altered through biochemical alterations known as [[DNA methylation]].<ref name=":22">{{cite journal | vauthors = Wajed SA, Laird PW, DeMeester TR | title = DNA methylation: an alternative pathway to cancer | journal = Annals of Surgery | volume = 234 | issue = 1 | pages = 10–20 | date = July 2001 | pmid = 11420478 | pmc = 1421942 | doi = 10.1097/00000658-200107000-00003 }}</ref> 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.<ref>{{cite journal | vauthors = Baylin SB | title = DNA methylation and gene silencing in cancer | journal = Nature Clinical Practice. Oncology | volume = 2 | issue = Suppl 1 | pages = S4-11 | date = December 2005 | pmid = 16341240 | doi = 10.1038/ncponc0354 | s2cid = 19361179 }}</ref>

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.<ref>{{cite journal | vauthors = Delbridge AR, Valente LJ, Strasser A | title = The role of the apoptotic machinery in tumor suppression | journal = Cold Spring Harbor Perspectives in Biology | volume = 4 | issue = 11 | pages = a008789 | date = November 2012 | pmid = 23125015 | pmc = 3536334 | doi = 10.1101/cshperspect.a008789 }}</ref> 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.<ref name=":10" />   In addition to DNA methylation, other epigenetic modifications like [[Histone acetylation and deacetylation|histone deacetylation]] or chromatin-binding proteins can prevent DNA polymerase from effectively transcribing desired sequences, such as ones containing tumor suppressor genes.{{cn|date=March 2025}}

== 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 quantitative trait loci|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 vector|viral]] and non-viral delivery methods.<ref name=":10" />

=== Viral methods ===
The viral method of transferring genetic material harnesses the power of [[virus]]es.<ref name=":10" />  By using viruses that are durable to genetic material alterations, viral methods of gene therapy for tumor suppressor genes have shown to be successful.<ref name=":8">{{cite journal | vauthors = Nayerossadat N, Maedeh T, Ali PA | title = Viral and nonviral delivery systems for gene delivery | journal = Advanced Biomedical Research | volume = 1 | pages = 27 | date = 2012-07-06 | pmid = 23210086 | pmc = 3507026 | doi = 10.4103/2277-9175.98152 | doi-access = free }}</ref> In this method, [[Vectors in gene therapy|vectors]] from viruses are used. The two most commonly used vectors are [[adenoviral]] [[Vectors in gene therapy|vectors]] and [[Adeno-associated virus|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.<ref name=":10" /><ref name=":7">{{cite journal | vauthors = Guo XE, Ngo B, Modrek AS, Lee WH | title = Targeting tumor suppressor networks for cancer therapeutics | journal = Current Drug Targets | volume = 15 | issue = 1 | pages = 2–16 | date = January 2014 | pmid = 24387338 | pmc = 4032821 | doi = 10.2174/1389450114666140106095151 }}</ref> Before the vectors are inserted into the [[Neoplasm|tumors]] of the host, they are prepared by having the parts of their genome that control [[DNA replication|replication]] either [[Mutation|mutated]] or deleted. This makes them safer for [[Insertion (genetics)|insertion]]. Then, the desired genetic material is inserted and [[ligation (molecular biology)|ligated]] to the vector.<ref name=":8" /> In the case with tumor suppressor genes, genetic material which encodes [[p53]] has been used successfully, which after application, has shown reduction in [[Neoplasm|tumor]] growth or [[Cell growth|proliferation]].<ref name=":7" /><ref name=":9">{{cite journal | vauthors = Morris LG, Chan TA | title = Therapeutic targeting of tumor suppressor genes | journal = Cancer | volume = 121 | issue = 9 | pages = 1357–1368 | date = May 2015 | pmid = 25557041 | pmc = 4526158 | doi = 10.1002/cncr.29140 }}</ref>

=== Non-viral methods ===
The non-viral method of transferring genetic material is used less often than the viral method.<ref name=":10" /><ref name=":7" /> However, the non-viral method is a more cost-effective, safer, available method of gene delivery not to mention that non-viral methods have shown to induce fewer host [[Immune system|immune]] responses and possess no restrictions on size or length of the transferable genetic material.<ref name=":10" />  Non-viral gene therapy uses either chemical or physical methods to introduce genetic material to the desired [[Cell (biology)|cells]].<ref name=":10" /><ref name=":7" /> The chemical methods are used primarily for tumor suppressor gene introduction and are divided into two categories which are naked [[plasmid]] or [[liposome]]-coated plasmids.<ref name=":7" /> The naked plasmid strategy has garnered interest because of its easy to use methods.<ref name=":10" />  Direct [[Injection (medicine)|injection]] into the [[muscle]]s allows for the plasmid to be taken up into the cell of possible tumors where the genetic material of the plasmid can be incorporated into the genetic material of the tumor cells and revert any previous damage done to tumor suppressor genes.<ref name=":10" /><ref name=":7" /> The liposome-coated plasmid method has recently also been of interest since they produce relatively low host [[immune response]] and are efficient with cellular targeting.<ref name=":7" /> The positively charged [[Vesicle (biology and chemistry)|capsule]] in which the genetic material is packaged helps with [[electrostatic attraction]] to the negatively charged [[Cell membrane|membranes]] of the cells as well as the negatively charged [[DNA]] of the tumor cells.<ref name=":10" /><ref name=":7" /> In this way, non-viral methods of gene therapy are highly effective in restoring tumor suppressor gene function to tumor cells that have either partially or entirely lost this function.{{cn|date=March 2025}}

=== Limitations ===
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.<ref name=":9" />

==Examples==
{| class="wikitable"
|+
|-
! Gene !! Original Function !! Two-Hit? !! Associated Carcinomas
|-
| [[Rb gene|Rb]]|| DNA Replication, cell division and death || Yes || Retinoblastoma<ref name=":6" />
|-
| [[P53 gene|p53]]|| Apoptosis || No{{Citation needed|date=April 2021}} || Half of all known malignancies<ref name=":6" />
|-
| [[VHL (gene)|VHL]]||Cell division, death, and differentiation
| Yes ||Kidney Cancer<ref name=":10" />
|-
| [[APC gene|APC]]||DNA damage, cell division, migration, adhesion, death
| Yes ||Colorectal Cancer<ref name=":10" />
|-
| [[BRCA2 (gene)|BRCA2]]||Cell division and death, and repair of double-stranded DNA breaks
| Yes ||Breast/Ovarian Cancer<ref name=":6" />
|-
|[[NF1 (gene)|NF1]]
|Cell differentiation, division, development, RAS signal transduction
|No
|Nerve tumors, Neuroblastoma<ref name=":10" />
|-
|[[PTCH1 (gene)|PTCH]]
|[[Hedgehog signaling pathway|Hedgehog signaling]]
|No
|Medulloblastoma, Basal Cell Carcinoma<ref name=":6" />
|}
<ref name=":10">{{Cite web|title=Tumor Suppressor (TS) Genes and the Two-Hit Hypothesis {{!}} Learn Science at Scitable|url=https://www.nature.com/scitable/topicpage/tumor-suppressor-ts-genes-and-the-two-887/|access-date=2020-10-27|website=www.nature.com|language=en}}</ref>
* '''Retinoblastoma protein (pRb)'''. [[Retinoblastoma protein|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.<ref name=":0" /> Specifically pRb prevents the cell cycle progression from [[G1 phase]] into the [[S phase]] by binding to [[E2F1|E2F]] and repressing the necessary gene transcription.<ref>{{Cite web|url=http://dpuadweb.depauw.edu/cfornari_web/DISGEN/retinoblastoma_website/public_html/protein.htm|title=RETINOBLASTOMA: Protein|website=dpuadweb.depauw.edu|access-date=2019-11-21}}</ref> 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.<ref name=":02">{{cite journal | vauthors = Harris CC | title = Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies | journal = Journal of the National Cancer Institute | volume = 88 | issue = 20 | pages = 1442–1455 | date = October 1996 | pmid = 8841019 | doi = 10.1093/jnci/88.20.1442 | doi-access = free }}</ref> Mutated p53 is involved in many human cancers, of the 6.5 million cancer diagnoses each year about 37% are connected to p53 mutations.<ref name=":02" /> This makes it a popular target for new cancer therapies. Homozygous loss of p53 is found in 65% of colon cancers, 30–50% of breast cancers, and 50% of lung cancers. Mutated p53 is also involved in the pathophysiology of leukemias, lymphomas, sarcomas, and neurogenic tumors. Abnormalities of the p53 gene can be inherited in [[Li-Fraumeni syndrome]] (LFS), which increases the risk of developing various types of cancers.
* '''BCL2.''' [[Bcl-2|BCL2]] is a family of proteins that are involved in either inducing or inhibiting apoptosis.<ref name=":3">{{Cite web|url=http://atlasgeneticsoncology.org/Genes/GC_BCL2.html|title=BCL2 (B-Cell Leukemia/Lymphoma 2)|website=atlasgeneticsoncology.org|access-date=2019-11-21|archive-date=2021-06-14|archive-url=https://web.archive.org/web/20210614064435/https://www.atlasgeneticsoncology.org/Genes/GC_BCL2.html|url-status=dead}}</ref> The main function is involved in maintaining the composition of the [[Mitochondrion|mitochondria]] membrane, and preventing [[cytochrome c]] release into the cytosol.<ref name=":3" /> When cytochrome c is released from the mitochondria it starts a signaling cascade to begin apoptosis.<ref>{{cite journal | vauthors = Goodsell DS | title = The molecular perspective: cytochrome C and apoptosis | journal = The Oncologist | volume = 9 | issue = 2 | pages = 226–227 | date = 2004-04-01 | pmid = 15047927 | doi = 10.1634/theoncologist.9-2-226 }}</ref>
* '''SWI/SNF. [[SWI/SNF]]''' is a [[chromatin]] remodeling complex, which is lost in about 20% of tumors.<ref name=":4">{{cite journal | vauthors = Shain AH, Pollack JR | title = The spectrum of SWI/SNF mutations, ubiquitous in human cancers | journal = PLOS ONE | volume = 8 | issue = 1 | pages = e55119 | date = 2013 | pmid = 23355908 | pmc = 3552954 | doi = 10.1371/journal.pone.0055119 | bibcode = 2013PLoSO...855119S | doi-access = free }}</ref> The complex consists of 10-15 subunits encoded by 20 different genes.<ref name=":4" /> 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 [[nucleosome]]s, which condenses DNA, allowing for transcription or block transcription from occurring for certain genes.<ref name=":4" /> 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 [[Von Hippel–Lindau tumor suppressor|pVHL]], [[APC (gene)|APC]], [[CD95]], [[ST5 (gene)|ST5]], [[YPEL3]], [[ST7]], and [[ST14]], [[p16]], [[BRCA2]].<ref>{{Cite web|url=https://www.letstalkacademy.com/publication/read/tumour-suppressor-genes-in-cancer|title=TUMOUR SUPPRESSOR GENES IN CANCER|website=www.letstalkacademy.com|access-date=2019-11-21}}</ref>
{{Further|DLD/NP1}}

== See also ==
* [[Anticancer gene]]
* [[Metastasis suppressor]]
* [[APC (gene)|Adenomatosis polyposis coli]]
* [[Oncogene]]
* [[Cancer]]
* [[DNA repair]]
* [[Signal transduction]]
* [[Von Hippel Lindau Binding protein 1]]
* [[BRCA1]]
* [[p53]]

== References ==
{{Reflist}}

== External links ==
* [http://researchnews.osu.edu/archive/lungcagn.htm TCF21 gene discovery at Ohio State University]
* [http://www.sdbonline.org/fly/aignfam/tumorsup.htm ''Drosophila'' Oncogenes and Tumor Suppressors - The Interactive Fly]
* [http://bioinfo.mc.vanderbilt.edu/TSGene/ Tumor Suppressor Gene Database, published in 2012] {{Webarchive|url=https://web.archive.org/web/20140109051019/http://bioinfo.mc.vanderbilt.edu/TSGene/ |date=2014-01-09 }}

{{Tumors}}
{{Tumor suppressor genes}}

{{DEFAULTSORT:Tumor Suppressor Gene}}
[[Category:Carcinogenesis]]
[[Category:Tumor suppressor genes]]