840:, 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. 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
282:, 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. Non-hereditary retinoblastoma involves two mutations, one on each allele. 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.
258:
31:
182:. 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. 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
266:
242:, which states both alleles that code for a particular protein must be affected before an effect is manifested. 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
654:
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
624:
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. The liposome-coated plasmid method has recently also been of
277:
for cases of retinoblastoma. 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
499:
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
487:
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
443:. 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.,
874:
remodeling complex, which is lost in about 20% of tumors. The complex consists of 10-15 subunits encoded by 20 different genes. 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
655:
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.
81:, 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
85:. Lastly, landscaper genes regulate growth by contributing to the surrounding environment, and when mutated, can cause an environment that promotes unregulated proliferation. The classification schemes are evolving as medical advances are being made from fields including
883:
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
598:
The non-viral method of transferring genetic material is used less often than the viral method. 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
488:
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
519:, 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
500:
neoplastic tissue methylation in order to one day identify early treatment options for gene modification that can silence the tumor suppressor gene. In addition to DNA methylation, other epigenetic modifications like
293:, meaning that a mutated p53 protein can prevent the function of the natural protein produced from the non-mutated allele. Other tumor-suppressor genes that do not follow the two-hit rule are those that exhibit
645:
of the tumor cells. 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.
603:
responses and possess no restrictions on size or length of the transferable genetic material. Non-viral gene therapy uses either chemical or physical methods to introduce genetic material to the desired
2835:
454:
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
879:, which condenses DNA, allowing for transcription or block transcription from occurring for certain genes. Mutating this ability could cause genes to be turned on or off at the wrong times.
66:. 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
496:. 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.
1000:
535:. By using viruses that are durable to genetic material alterations, viral methods of gene therapy for tumor suppressor genes have shown to be successful. In this method,
2828:
333:. While tumor suppressor genes have the same main function, they have various mechanisms of action, that their transcribed products perform, which include the following:
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2821:
113:
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
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gene is a gatekeeper gene that blocks cell proliferation, regulates cell division and cell death. Specifically pRb prevents the cell cycle progression from
853:
is a family of proteins that are involved in either inducing or inhibiting apoptosis. The main function is involved in maintaining the composition of the
504:
or chromatin-binding proteins can prevent DNA polymerase from effectively transcribing desired sequences, such as ones containing tumor suppressor genes.
3322:
1721:
Rahman N, Scott RH (April 2007). "Cancer genes associated with phenotypes in monoallelic and biallelic mutation carriers: new lessons from old players".
483:. Methylation is an example of epigenetic modifications, which commonly regulate expression in mammalian genes. The addition of a methyl group to either
144:
from both parents and upon growth, a majority of these hybrid cells did not have the capability of developing tumors within animals. The suppression of
3166:
3161:
1274:
Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B (August 1990). "Suppression of human colorectal carcinoma cell growth by wild-type p53".
156:
had inhibitory actions to stop tumor growth. This initial hypothesis eventually lead to the discovery of the first classic tumor suppressor gene by
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885:
515:
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
202:
that were needed to fully lose tumor suppressor properties. This finding formed the basis of the two-hit hypothesis. In order to verify that the
1008:
501:
1065:
406:. 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.,
970:
2234:
1694:
Markowitz S (November 2000). "DNA repair defects inactivate tumor suppressor genes and induce hereditary and sporadic colon cancers".
516:
608:. The chemical methods are used primarily for tumor suppressor gene introduction and are divided into two categories which are naked
198:. The more sporadic occurrence of unilateral development of retinoblastoma was hypothesized to develop much later in life due to two
3018:
2436:
384:
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release into the cytosol. When cytochrome c is released from the mitochondria it starts a signaling cascade to begin apoptosis.
630:
38:. Many tumor suppressors work to regulate the cycle at specific checkpoints in order to prevent damaged cells from replicating.
2880:
329:. In most cases, tumor suppressor proteins inhibit the same cell regulatory pathways that are stimulated by the products of
2751:
121:
playing a role in decreasing cellular growth and development of cells. This idea was not solidified until experiments by
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1969:
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3132:
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and repressing the necessary gene transcription. This prevents the cell from replicating its DNA if there is damage.
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or survival. Inactivation of tumor suppressor genes therefore leads to tumor development by eliminating negative
67:
70:
for these genes may be even more significant in the development of human cancers, compared to the activation of
2999:
2885:
2611:
2569:
634:
616:-coated plasmids. The naked plasmid strategy has garnered interest because of its easy to use methods. Direct
122:
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3225:
2903:
2704:
2668:
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543:
536:
459:
455:
2192:"Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies"
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3411:
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804:
547:
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Expression of genes, including tumor suppressors, can be altered through biochemical alterations known as
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161:
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germ-line but not display the disease. Knudson observed that the age of onset of retinoblastoma followed
3101:
2912:
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429:
309:, a cell-cycle inhibitor, that when one allele is mutated causes increased carcinogen susceptibility.
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application is relatively safe compared to other vectors. Before the vectors are inserted into the
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There are exceptions to the two-hit rule for tumor suppressors, such as certain mutations in the
239:
110:
1073:
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for the Rb gene. This deletion caused increased tumor growth in retinoblastoma, suggesting that
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345:. If these genes are not expressed, the cell cycle does not continue, effectively inhibiting
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2019:
2009:
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Leiderman YI, Kiss S, Mukai S (2007). "Molecular genetics of RB1--the retinoblastoma gene".
1406:
1346:
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1213:
1203:
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215:
1166:
Cooper, G. M. (2000). Tumor
Suppressor Genes. The Cell: A Molecular Approach. 2nd Edition.
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during cell division and replication. If the cell grows uncontrollably, it will result in
2320:
1663:
1636:
1334:
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2724:
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1997:
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1827:
1802:
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to the vector. In the case with tumor suppressor genes, genetic material which encodes
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223:
207:
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126:
78:
59:
2242:
2079:
1218:
1183:
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3295:
3269:
2865:
2528:
1818:
1559:
Nayak SK, Panesar PS, Kumar H (2009). "p53-Induced apoptosis and inhibitors of p53".
854:
638:
600:
417:
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346:
286:
279:
211:
137:
2394:
1970:"Tumor Suppressor (TS) Genes and the Two-Hit Hypothesis | Learn Science at Scitable"
1879:
1680:
1463:
1251:"Tumor Suppressor (TS) Genes and the Two-Hit Hypothesis | Learn Science at Scitable"
1144:
3356:
3116:
2469:
2389:
2263:
Goodsell DS (2004-04-01). "The molecular perspective: cytochrome C and apoptosis".
858:
778:
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of the host, they are prepared by having the parts of their genome that control
489:
141:
133:
94:
17:
1572:
1188:
Proceedings of the
National Academy of Sciences of the United States of America
811:; however, recent evidence has also implicated pRb as a tumor-survival factor.
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2586:
2523:
2487:
2208:
2191:
1769:
1612:
1595:
1447:
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1167:
1028:
Weinberg, Robert A (2014). "The
Biology of Cancer." Garland Science, page 231.
960:
945:
897:
889:
876:
762:
714:
540:
493:
425:
380:
342:
306:
35:
1520:"BRCA1, a 'complex' protein involved in the maintenance of genomic stability"
2756:
2642:
2627:
2508:
2492:
2014:
1596:"Metastasis-suppressor genes: a review and perspective on an emerging field"
1295:
871:
582:
has been used successfully, which after application, has shown reduction in
403:
330:
106:
82:
30:
2402:
2348:
2284:
2149:
2097:
2033:
1928:
1871:
1850:
Baylin SB (December 2005). "DNA methylation and gene silencing in cancer".
1836:
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1621:
1580:
1545:
1504:
1455:
1420:
1136:
2217:
1360:
1303:
1227:
1208:
170:, a pediatrician and cancer geneticist, proposed that in order to develop
3645:
3390:
3385:
3023:
2848:
2746:
2637:
2596:
2581:
2454:
2446:
1754:"Double agents: genes with both oncogenic and tumor-suppressor functions"
1730:
950:
816:
730:
698:
613:
583:
567:
559:
551:
531:
The viral method of transferring genetic material harnesses the power of
318:
247:
235:
219:
203:
187:
183:
175:
90:
71:
1594:
Yoshida BA, Sokoloff MM, Welch DR, Rinker-Schaeffer CW (November 2000).
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2632:
2131:
1863:
1536:
1519:
924:
866:
844:(LFS), which increases the risk of developing various types of cancers.
820:
682:
609:
555:
484:
365:
178:
are required to lose functional copies of both the Rb genes to lead to
1411:
1394:
1319:"The murine gene p27Kip1 is haplo-insufficient for tumour suppression"
3425:
3338:
2518:
2450:
1395:"Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview"
955:
767:
Cell differentiation, division, development, RAS signal transduction
621:
396:
195:
63:
1479:"Molecular pathways: targeting the TGF-β pathway for cancer therapy"
1317:
Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ (November 1998).
265:
3635:
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3547:
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3458:
3279:
3074:
3069:
3035:
3028:
2956:
1342:
975:
917:
901:
850:
751:
Cell division and death, and repair of double-stranded DNA breaks
629:
and are efficient with cellular targeting. The positively charged
532:
433:
388:
264:
256:
149:
118:
3615:
3610:
3575:
3497:
3274:
3014:
2482:
2305:"The spectrum of SWI/SNF mutations, ubiquitous in human cancers"
1001:"Oncogenes and tumor suppressor genes | American Cancer Society"
909:
893:
824:
448:
368:
or developmental signals that inhibit cell proliferation (e.g.,
55:
2817:
2418:
148:
in these hybrid cells prompted researchers to hypothesize that
3559:
3416:
3406:
3195:
980:
913:
905:
837:
642:
579:
539:
from viruses are used. The two most commonly used vectors are
463:
444:
440:
407:
392:
354:
109:
and their ability to deregulate cellular processes related to
2064:"Targeting tumor suppressor networks for cancer therapeutics"
807:
was the first tumor-suppressor protein discovered in human
554:
genetic manipulation of these types of vectors is easy and
1895:"The role of the apoptotic machinery in tumor suppression"
1184:"Mutation and cancer: statistical study of retinoblastoma"
27:
Gene that inhibits expression of the tumorigenic phenotype
1998:"Viral and nonviral delivery systems for gene delivery"
1893:
Delbridge AR, Valente LJ, Strasser A (November 2012).
735:
DNA damage, cell division, migration, adhesion, death
2398:
1637:"Cell adhesion system and human cancer morphogenesis"
633:
in which the genetic material is packaged helps with
574:. Then, the desired genetic material is inserted and
214:
were conducted to observe the effect of deleting the
1382:(2nd ed.). Sunderland (MA): Sinauer Associates.
3628:
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3262:
3253:
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3188:
3179:
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3125:
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3100:
3091:
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3007:
2998:
2978:
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2940:
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2911:
2902:
2873:
2864:
2855:
2770:
2723:
2681:
2656:
2620:
2542:
2501:
2468:
2461:
1803:"DNA methylation: an alternative pathway to cancer"
420:prevent tumor cells from dispersing, block loss of
77:TSGs can be grouped into the following categories:
2403:Tumor Suppressor Gene Database, published in 2012
2116:"Therapeutic targeting of tumor suppressor genes"
2062:Guo XE, Ngo B, Modrek AS, Lee WH (January 2014).
625:interest since they produce relatively low host
1996:Nayerossadat N, Maedeh T, Ali PA (2012-07-06).
1393:Wang LH, Wu CF, Rajasekaran N, Shin YK (2018).
641:of the cells as well as the negatively charged
1801:Wajed SA, Laird PW, DeMeester TR (July 2001).
1477:Smith AL, Robin TP, Ford HL (September 2012).
238:, tumor suppressor genes generally follow the
2829:
2430:
2390:TCF21 gene discovery at Ohio State University
117:gave way to another possible genetic idea of
8:
160:, known as the Rb gene, which codes for the
1168:https://www.ncbi.nlm.nih.gov/books/NBK9894/
439:Proteins involved in repairing mistakes in
389:breast cancer type 1 susceptibility protein
206:of tumor suppressor genes causes increased
3598:
3532:
3482:
3448:
3370:
3361:
3312:
3259:
3230:
3185:
3151:
3106:
3097:
3059:
3004:
2975:
2946:
2917:
2908:
2870:
2861:
2836:
2822:
2814:
2465:
2437:
2423:
2415:
1899:Cold Spring Harbor Perspectives in Biology
1042:"Glossary of Cancer Genetics (side-frame)"
719:Cell division, death, and differentiation
186:of one loss of function mutation to an RB
2338:
2328:
2207:
2139:
2087:
2023:
2013:
1918:
1826:
1777:
1662:
1652:
1611:
1535:
1494:
1410:
1350:
1217:
1207:
1126:
379:Checkpoint-control proteins that trigger
2196:Journal of the National Cancer Institute
1600:Journal of the National Cancer Institute
836:, a caretaker gene, encodes the protein
687:DNA Replication, cell division and death
662:
222:of a tumor suppressor gene can increase
29:
1964:
1962:
1960:
1958:
992:
321:by most tumor suppressor genes inhibit
210:, interstitial deletion experiments on
162:retinoblastoma tumor suppressor protein
2185:
2183:
1956:
1954:
1952:
1950:
1948:
1946:
1944:
1942:
1940:
1938:
1518:Savage KI, Harkin DP (February 2015).
791:Medulloblastoma, Basal Cell Carcinoma
570:or deleted. This makes them safer for
2298:
2296:
2294:
2229:
2227:
2109:
2107:
2057:
2055:
2053:
2051:
2049:
2047:
2045:
2043:
1991:
1989:
337:Intracellular proteins, that control
7:
1752:Shen L, Shi Q, Wang W (March 2018).
1399:Cellular Physiology and Biochemistry
1245:
1243:
1241:
1239:
1237:
1177:
1175:
1162:
1160:
1158:
1156:
1154:
1104:
1102:
1100:
1098:
1096:
1094:
1092:
1090:
1036:
1034:
140:to make hybrid cells. Each cell had
2363:"TUMOUR SUPPRESSOR GENES IN CANCER"
2235:"BCL2 (B-Cell Leukemia/Lymphoma 2)"
971:Von Hippel Lindau Binding protein 1
289:. p53 mutations can function as a
1852:Nature Clinical Practice. Oncology
1654:10.1111/j.1349-7006.2003.tb01485.x
1635:Hirohashi S, Kanai Y (July 2003).
269:Illustration of two-hit hypothesis
25:
2080:10.2174/1389450114666140106095151
1111:"Principles of Tumor Suppression"
1819:10.1097/00000658-200107000-00003
523:and non-viral delivery methods.
2114:Morris LG, Chan TA (May 2015).
709:Half of all known malignancies
1725:. 16 Spec No 1 (R1): R60–R66.
1380:The Cell: A Molecular Approach
428:. These proteins are known as
387:or chromosomal defects (e.g.,
1:
2752:Clonally transmissible cancer
2303:Shain AH, Pollack JR (2013).
2277:10.1634/theoncologist.9-2-226
1496:10.1158/1078-0432.CCR-11-3224
1128:10.1016/S0092-8674(03)01075-4
449:DNA mismatch repair protein 2
132:Within Harris's experiments,
3093:Intracellular signaling P+Ps
2330:10.1371/journal.pone.0055119
2002:Advanced Biomedical Research
1696:Journal of Clinical Oncology
1066:"Cancer Genetics - CuboCube"
801:Retinoblastoma protein (pRb)
773:Nerve tumors, Neuroblastoma
416:. Some proteins involved in
1911:10.1101/cshperspect.a008789
1561:Current Medicinal Chemistry
946:Adenomatosis polyposis coli
341:of a specific stage of the
261:Models of tumor suppression
3688:
3147:TGF beta signaling pathway
3055:JAK-STAT signaling pathway
2971:TGF beta signaling pathway
2942:Hedgehog signaling pathway
2783:Index of oncology articles
2190:Harris CC (October 1996).
1573:10.2174/092986709788681976
1109:Sherr, Charles J. (2004).
922:
637:to the negatively charged
374:adenomatous polyposis coli
370:transforming growth factor
194:on its functional Rb gene
127:somatic cell hybridization
3181:Akt/PKB signaling pathway
2239:atlasgeneticsoncology.org
2164:"RETINOBLASTOMA: Protein"
1770:10.1038/s41389-018-0034-x
1448:10.1080/08820530701745165
1436:Seminars in Ophthalmology
1182:Knudson AG (April 1971).
857:membrane, and preventing
3000:Receptor tyrosine kinase
1723:Human Molecular Genetics
1483:Clinical Cancer Research
1376:"Tumor Suppressor Genes"
635:electrostatic attraction
3226:Hippo signaling pathway
2705:Prostate cancer staging
2669:Paraneoplastic syndrome
2367:www.letstalkacademy.com
2209:10.1093/jnci/88.20.1442
2015:10.4103/2277-9175.98152
1613:10.1093/jnci/92.21.1717
1296:10.1126/science.2144057
136:were fused with normal
3672:Tumor suppressor genes
3241:Neurofibromin 2/Merlin
2845:Tumor suppressor genes
2743:Tumor suppressor genes
2710:Gleason grading system
2664:Precancerous condition
757:Breast/Ovarian Cancer
677:Associated Carcinomas
430:metastasis suppressors
383:arrest in response to
305:. Another example is
270:
262:
250:alleles are typically
39:
3102:Wnt signaling pathway
2913:Wnt signaling pathway
2762:Carcinogenic bacteria
2502:Malignant progression
1702:(21 Suppl): 75S–80S.
1209:10.1073/pnas.68.4.820
941:Metastasis suppressor
923:Further information:
508:Clinical significance
502:histone deacetylation
475:Epigenetic influences
402:Proteins that induce
268:
260:
44:tumor suppressor gene
33:
3528:Transcription factor
2715:Dukes classification
2068:Current Drug Targets
842:Li-Fraumeni syndrome
297:, including PTCH in
220:loss or inactivation
190:followed by a later
125:were conducted with
3603:Apoptosis inhibitor
2986:TGF beta receptor 2
2534:Sentinel lymph node
2321:2013PLoSO...855119S
2168:dpuadweb.depauw.edu
1335:1998Natur.396..177F
1288:1990Sci...249..912B
1200:1971PNAS...68..820K
1046:www.cancerindex.org
966:Signal transduction
664:
327:regulatory proteins
2582:Respiratory system
2408:2014-01-09 at the
2132:10.1002/cncr.29140
1864:10.1038/ncponc0354
1858:(Suppl 1): S4-11.
1731:10.1093/hmg/ddm026
1537:10.1111/febs.13150
1374:Cooper GM (2000).
784:Hedgehog signaling
741:Colorectal Cancer
663:
422:contact inhibition
362:signal transducers
323:cell proliferation
295:haploinsufficiency
280:2nd order kinetics
271:
263:
240:two-hit hypothesis
230:Two-hit hypothesis
152:within the normal
111:cell proliferation
40:
3654:
3653:
3624:
3623:
3588:
3587:
3584:
3583:
3522:
3521:
3472:
3471:
3434:
3433:
3351:
3350:
3347:
3346:
3304:
3303:
3249:
3248:
3220:
3219:
3175:
3174:
3141:
3140:
3087:
3086:
3083:
3082:
3049:
3048:
2994:
2993:
2965:
2964:
2936:
2935:
2898:
2897:
2894:
2893:
2811:
2810:
2798:Cancer and nausea
2677:
2676:
2514:Carcinoma in situ
2202:(20): 1442–1455.
1807:Annals of Surgery
1606:(21): 1717–1730.
1567:(21): 2627–2640.
1489:(17): 4514–4521.
1412:10.1159/000495956
1329:(6707): 177–180.
1282:(4971): 912–915.
795:
794:
671:Original Function
594:Non-viral methods
291:dominant negative
246:, whereas mutant
200:de novo mutations
176:allelic mutations
105:The discovery of
87:molecular biology
58:that regulates a
16:(Redirected from
3679:
3599:
3533:
3483:
3478:Ubiquitin ligase
3449:
3371:
3362:
3313:
3260:
3255:MAPK/ERK pathway
3231:
3186:
3152:
3107:
3098:
3060:
3005:
2976:
2947:
2918:
2909:
2871:
2862:
2838:
2831:
2824:
2815:
2612:Endocrine system
2577:Digestive system
2466:
2439:
2432:
2425:
2416:
2377:
2376:
2374:
2373:
2359:
2353:
2352:
2342:
2332:
2300:
2289:
2288:
2260:
2254:
2253:
2251:
2250:
2241:. Archived from
2231:
2222:
2221:
2211:
2187:
2178:
2177:
2175:
2174:
2160:
2154:
2153:
2143:
2126:(9): 1357–1368.
2111:
2102:
2101:
2091:
2059:
2038:
2037:
2027:
2017:
1993:
1984:
1983:
1981:
1980:
1966:
1933:
1932:
1922:
1890:
1884:
1883:
1847:
1841:
1840:
1830:
1798:
1792:
1791:
1781:
1749:
1743:
1742:
1718:
1712:
1711:
1691:
1685:
1684:
1666:
1656:
1632:
1626:
1625:
1615:
1591:
1585:
1584:
1556:
1550:
1549:
1539:
1524:The FEBS Journal
1515:
1509:
1508:
1498:
1474:
1468:
1467:
1431:
1425:
1424:
1414:
1405:(6): 2647–2693.
1390:
1384:
1383:
1371:
1365:
1364:
1354:
1314:
1308:
1307:
1271:
1265:
1264:
1262:
1261:
1247:
1232:
1231:
1221:
1211:
1179:
1170:
1164:
1149:
1148:
1130:
1106:
1085:
1084:
1082:
1081:
1072:. Archived from
1070:www.cubocube.com
1062:
1056:
1055:
1053:
1052:
1038:
1029:
1026:
1020:
1019:
1017:
1016:
1007:. Archived from
997:
665:
548:adeno-associated
319:proteins encoded
287:p53 gene product
212:chromosome 13q14
204:loss of function
192:de novo mutation
68:loss of function
21:
18:Tumor suppressor
3687:
3686:
3682:
3681:
3680:
3678:
3677:
3676:
3657:
3656:
3655:
3650:
3629:Other/ungrouped
3620:
3580:
3564:
3518:
3502:
3468:
3430:
3395:
3343:
3327:
3300:
3296:Neurofibromin 1
3284:
3245:
3216:
3200:
3171:
3137:
3121:
3079:
3045:
2990:
2961:
2932:
2890:
2851:
2842:
2812:
2807:
2766:
2719:
2673:
2652:
2616:
2538:
2497:
2457:
2443:
2410:Wayback Machine
2386:
2381:
2380:
2371:
2369:
2361:
2360:
2356:
2302:
2301:
2292:
2262:
2261:
2257:
2248:
2246:
2233:
2232:
2225:
2189:
2188:
2181:
2172:
2170:
2162:
2161:
2157:
2113:
2112:
2105:
2061:
2060:
2041:
1995:
1994:
1987:
1978:
1976:
1968:
1967:
1936:
1905:(11): a008789.
1892:
1891:
1887:
1849:
1848:
1844:
1800:
1799:
1795:
1751:
1750:
1746:
1720:
1719:
1715:
1693:
1692:
1688:
1634:
1633:
1629:
1593:
1592:
1588:
1558:
1557:
1553:
1517:
1516:
1512:
1476:
1475:
1471:
1433:
1432:
1428:
1392:
1391:
1387:
1373:
1372:
1368:
1316:
1315:
1311:
1273:
1272:
1268:
1259:
1257:
1249:
1248:
1235:
1181:
1180:
1173:
1165:
1152:
1108:
1107:
1088:
1079:
1077:
1064:
1063:
1059:
1050:
1048:
1040:
1039:
1032:
1027:
1023:
1014:
1012:
999:
998:
994:
989:
936:Anticancer gene
932:
927:
693:Retinoblastoma
661:
652:
627:immune response
596:
529:
510:
481:DNA methylation
477:
460:NOTCH receptors
339:gene expression
315:
299:medulloblastoma
232:
103:
79:caretaker genes
28:
23:
22:
15:
12:
11:
5:
3685:
3683:
3675:
3674:
3669:
3667:Carcinogenesis
3659:
3658:
3652:
3651:
3649:
3648:
3643:
3638:
3632:
3630:
3626:
3625:
3622:
3621:
3619:
3618:
3613:
3607:
3605:
3596:
3590:
3589:
3586:
3585:
3582:
3581:
3579:
3578:
3572:
3570:
3566:
3565:
3563:
3562:
3557:
3556:
3555:
3550:
3539:
3537:
3530:
3524:
3523:
3520:
3519:
3517:
3516:
3510:
3508:
3504:
3503:
3501:
3500:
3495:
3489:
3487:
3480:
3474:
3473:
3470:
3469:
3467:
3466:
3461:
3455:
3453:
3446:
3436:
3435:
3432:
3431:
3429:
3428:
3419:
3414:
3409:
3403:
3401:
3397:
3396:
3394:
3393:
3388:
3383:
3377:
3375:
3368:
3359:
3353:
3352:
3349:
3348:
3345:
3344:
3342:
3341:
3335:
3333:
3329:
3328:
3326:
3325:
3319:
3317:
3310:
3306:
3305:
3302:
3301:
3299:
3298:
3292:
3290:
3286:
3285:
3283:
3282:
3277:
3272:
3266:
3264:
3257:
3251:
3250:
3247:
3246:
3244:
3243:
3237:
3235:
3228:
3222:
3221:
3218:
3217:
3215:
3214:
3208:
3206:
3202:
3201:
3199:
3198:
3192:
3190:
3183:
3177:
3176:
3173:
3172:
3170:
3169:
3164:
3158:
3156:
3149:
3143:
3142:
3139:
3138:
3136:
3135:
3129:
3127:
3123:
3122:
3120:
3119:
3113:
3111:
3104:
3095:
3089:
3088:
3085:
3084:
3081:
3080:
3078:
3077:
3072:
3066:
3064:
3057:
3051:
3050:
3047:
3046:
3044:
3043:
3038:
3033:
3032:
3031:
3026:
3011:
3009:
3002:
2996:
2995:
2992:
2991:
2989:
2988:
2982:
2980:
2973:
2967:
2966:
2963:
2962:
2960:
2959:
2953:
2951:
2944:
2938:
2937:
2934:
2933:
2931:
2930:
2924:
2922:
2915:
2906:
2900:
2899:
2896:
2895:
2892:
2891:
2889:
2888:
2883:
2877:
2875:
2868:
2866:Growth factors
2859:
2853:
2852:
2843:
2841:
2840:
2833:
2826:
2818:
2809:
2808:
2806:
2805:
2800:
2795:
2790:
2785:
2780:
2774:
2772:
2768:
2767:
2765:
2764:
2759:
2754:
2749:
2740:
2735:
2729:
2727:
2725:Carcinogenesis
2721:
2720:
2718:
2717:
2712:
2707:
2702:
2697:
2691:
2689:
2679:
2678:
2675:
2674:
2672:
2671:
2666:
2660:
2658:
2654:
2653:
2651:
2650:
2645:
2640:
2635:
2630:
2624:
2622:
2618:
2617:
2615:
2614:
2609:
2607:Nervous system
2604:
2599:
2594:
2589:
2584:
2579:
2574:
2573:
2572:
2570:nasopharyngeal
2567:
2562:
2557:
2546:
2544:
2540:
2539:
2537:
2536:
2531:
2526:
2521:
2516:
2511:
2505:
2503:
2499:
2498:
2496:
2495:
2490:
2485:
2480:
2474:
2472:
2463:
2459:
2458:
2444:
2442:
2441:
2434:
2427:
2419:
2413:
2412:
2400:
2392:
2385:
2384:External links
2382:
2379:
2378:
2354:
2290:
2271:(2): 226–227.
2265:The Oncologist
2255:
2223:
2179:
2155:
2103:
2039:
1985:
1974:www.nature.com
1934:
1885:
1842:
1793:
1744:
1713:
1686:
1647:(7): 575–581.
1641:Cancer Science
1627:
1586:
1551:
1530:(4): 630–646.
1510:
1469:
1442:(4): 247–254.
1426:
1385:
1366:
1309:
1266:
1255:www.nature.com
1233:
1194:(4): 820–823.
1171:
1150:
1121:(2): 235–246.
1086:
1057:
1030:
1021:
1005:www.cancer.org
991:
990:
988:
985:
984:
983:
978:
973:
968:
963:
958:
953:
948:
943:
938:
931:
928:
881:
880:
862:
845:
828:
823:by binding to
809:retinoblastoma
793:
792:
789:
786:
781:
775:
774:
771:
768:
765:
759:
758:
755:
752:
749:
743:
742:
739:
736:
733:
727:
726:
725:Kidney Cancer
723:
720:
717:
711:
710:
707:
704:
701:
695:
694:
691:
688:
685:
679:
678:
675:
672:
669:
660:
657:
651:
648:
595:
592:
528:
525:
509:
506:
476:
473:
472:
471:
452:
437:
424:, and inhibit
411:
400:
377:
358:
314:
311:
231:
228:
224:tumorigenicity
208:tumorigenicity
188:germ-line gene
180:tumorigenicity
172:retinoblastoma
168:Alfred Knudson
158:Alfred Knudson
146:tumorigenicity
102:
99:
26:
24:
14:
13:
10:
9:
6:
4:
3:
2:
3684:
3673:
3670:
3668:
3665:
3664:
3662:
3647:
3644:
3642:
3639:
3637:
3634:
3633:
3631:
3627:
3617:
3614:
3612:
3609:
3608:
3606:
3604:
3600:
3597:
3595:
3594:Mitochondrion
3591:
3577:
3574:
3573:
3571:
3567:
3561:
3558:
3554:
3551:
3549:
3546:
3545:
3544:
3541:
3540:
3538:
3534:
3531:
3529:
3525:
3515:
3512:
3511:
3509:
3505:
3499:
3496:
3494:
3491:
3490:
3488:
3484:
3481:
3479:
3475:
3465:
3462:
3460:
3457:
3456:
3454:
3450:
3447:
3445:
3441:
3437:
3427:
3423:
3420:
3418:
3415:
3413:
3410:
3408:
3405:
3404:
3402:
3398:
3392:
3389:
3387:
3384:
3382:
3379:
3378:
3376:
3372:
3369:
3367:
3363:
3360:
3358:
3354:
3340:
3337:
3336:
3334:
3330:
3324:
3321:
3320:
3318:
3314:
3311:
3309:Other/unknown
3307:
3297:
3294:
3293:
3291:
3287:
3281:
3278:
3276:
3273:
3271:
3268:
3267:
3265:
3261:
3258:
3256:
3252:
3242:
3239:
3238:
3236:
3232:
3229:
3227:
3223:
3213:
3210:
3209:
3207:
3203:
3197:
3194:
3193:
3191:
3187:
3184:
3182:
3178:
3168:
3165:
3163:
3160:
3159:
3157:
3153:
3150:
3148:
3144:
3134:
3131:
3130:
3128:
3124:
3118:
3115:
3114:
3112:
3108:
3105:
3103:
3099:
3096:
3094:
3090:
3076:
3073:
3071:
3068:
3067:
3065:
3061:
3058:
3056:
3052:
3042:
3039:
3037:
3034:
3030:
3027:
3025:
3022:
3021:
3020:
3016:
3013:
3012:
3010:
3006:
3003:
3001:
2997:
2987:
2984:
2983:
2981:
2977:
2974:
2972:
2968:
2958:
2955:
2954:
2952:
2948:
2945:
2943:
2939:
2929:
2926:
2925:
2923:
2919:
2916:
2914:
2910:
2907:
2905:
2901:
2887:
2884:
2882:
2879:
2878:
2876:
2872:
2869:
2867:
2863:
2860:
2858:
2854:
2850:
2846:
2839:
2834:
2832:
2827:
2825:
2820:
2819:
2816:
2804:
2801:
2799:
2796:
2794:
2791:
2789:
2786:
2784:
2781:
2779:
2776:
2775:
2773:
2769:
2763:
2760:
2758:
2755:
2753:
2750:
2748:
2744:
2741:
2739:
2736:
2734:
2731:
2730:
2728:
2726:
2722:
2716:
2713:
2711:
2708:
2706:
2703:
2701:
2698:
2696:
2693:
2692:
2690:
2688:
2684:
2680:
2670:
2667:
2665:
2662:
2661:
2659:
2655:
2649:
2646:
2644:
2641:
2639:
2636:
2634:
2631:
2629:
2626:
2625:
2623:
2619:
2613:
2610:
2608:
2605:
2603:
2600:
2598:
2595:
2593:
2590:
2588:
2585:
2583:
2580:
2578:
2575:
2571:
2568:
2566:
2563:
2561:
2560:oropharyngeal
2558:
2556:
2553:
2552:
2551:
2550:Head and neck
2548:
2547:
2545:
2541:
2535:
2532:
2530:
2529:Primary tumor
2527:
2525:
2522:
2520:
2517:
2515:
2512:
2510:
2507:
2506:
2504:
2500:
2494:
2491:
2489:
2486:
2484:
2481:
2479:
2476:
2475:
2473:
2471:
2470:Benign tumors
2467:
2464:
2460:
2456:
2452:
2448:
2440:
2435:
2433:
2428:
2426:
2421:
2420:
2417:
2411:
2407:
2404:
2401:
2399:
2397:
2393:
2391:
2388:
2387:
2383:
2368:
2364:
2358:
2355:
2350:
2346:
2341:
2336:
2331:
2326:
2322:
2318:
2315:(1): e55119.
2314:
2310:
2306:
2299:
2297:
2295:
2291:
2286:
2282:
2278:
2274:
2270:
2266:
2259:
2256:
2245:on 2021-06-14
2244:
2240:
2236:
2230:
2228:
2224:
2219:
2215:
2210:
2205:
2201:
2197:
2193:
2186:
2184:
2180:
2169:
2165:
2159:
2156:
2151:
2147:
2142:
2137:
2133:
2129:
2125:
2121:
2117:
2110:
2108:
2104:
2099:
2095:
2090:
2085:
2081:
2077:
2073:
2069:
2065:
2058:
2056:
2054:
2052:
2050:
2048:
2046:
2044:
2040:
2035:
2031:
2026:
2021:
2016:
2011:
2007:
2003:
1999:
1992:
1990:
1986:
1975:
1971:
1965:
1963:
1961:
1959:
1957:
1955:
1953:
1951:
1949:
1947:
1945:
1943:
1941:
1939:
1935:
1930:
1926:
1921:
1916:
1912:
1908:
1904:
1900:
1896:
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1076:on 2020-10-12
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589:
588:proliferation
585:
581:
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527:Viral methods
526:
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469:
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456:transcription
453:
450:
446:
442:
438:
435:
431:
427:
423:
419:
418:cell adhesion
415:
414:Cell adhesion
412:
409:
405:
401:
398:
394:
390:
386:
382:
378:
375:
371:
367:
364:for secreted
363:
360:Receptors or
359:
356:
352:
348:
347:cell division
344:
340:
336:
335:
334:
332:
328:
324:
320:
312:
310:
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296:
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197:
193:
189:
185:
181:
177:
173:
169:
165:
163:
159:
155:
151:
147:
143:
139:
138:somatic cells
135:
130:
128:
124:
120:
116:
112:
108:
100:
98:
96:
92:
88:
84:
80:
75:
73:
69:
65:
61:
57:
53:
52:anti-oncogene
49:
45:
37:
32:
19:
3117:Beta-catenin
2844:
2742:
2445:Overview of
2395:
2370:. Retrieved
2366:
2357:
2312:
2308:
2268:
2264:
2258:
2247:. Retrieved
2243:the original
2238:
2199:
2195:
2171:. Retrieved
2167:
2158:
2123:
2119:
2071:
2067:
2005:
2001:
1977:. Retrieved
1973:
1902:
1898:
1888:
1855:
1851:
1845:
1813:(1): 10–20.
1810:
1806:
1796:
1761:
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1369:
1326:
1322:
1312:
1279:
1275:
1269:
1258:. Retrieved
1254:
1191:
1187:
1118:
1114:
1078:. Retrieved
1074:the original
1069:
1060:
1049:. Retrieved
1045:
1024:
1013:. Retrieved
1009:the original
1004:
995:
882:
864:
859:cytochrome c
855:mitochondria
847:
833:
830:
812:
800:
796:
653:
597:
530:
513:Gene therapy
511:
498:
478:
372:(TGF)-β and
316:
303:neurofibroma
284:
275:A.G. Knudson
273:Proposed by
272:
233:
166:
154:somatic cell
131:
123:Henry Harris
115:tumor growth
104:
76:
51:
47:
43:
41:
2793:Cancer pain
2733:Cancer cell
2478:Hyperplasia
2074:(1): 2–16.
1758:Oncogenesis
877:nucleosomes
650:Limitations
564:replication
490:azacitidine
301:and NF1 in
184:inheritance
142:chromosomes
134:tumor cells
95:epigenetics
3661:Categories
3440:DNA repair
3366:Cell cycle
2881:c-Sis/PDGF
2738:Carcinogen
2602:Urogenital
2543:Topography
2524:Metastasis
2488:Pseudocyst
2462:Conditions
2396:Drosophila
2372:2019-11-21
2249:2019-11-21
2173:2019-11-21
1979:2020-10-27
1260:2019-10-06
1080:2019-11-19
1051:2019-11-19
1015:2019-09-26
987:References
961:DNA repair
586:growth or
541:adenoviral
517:expression
494:decitabine
426:metastasis
385:DNA damage
381:cell cycle
343:cell cycle
36:cell cycle
2849:Oncogenes
2757:Oncovirus
2747:oncogenes
2700:Ann Arbor
2643:Papilloma
2628:Carcinoma
2621:Histology
2565:laryngeal
2509:Dysplasia
2493:Hamartoma
1764:(3): 25.
872:chromatin
865:SWI/SNF.
819:into the
703:Apoptosis
639:membranes
620:into the
618:injection
572:insertion
550:vectors.
458:. (e.g.,
432:. (e.g.,
404:apoptosis
391:(BRCA1),
349:. (e.g.,
331:oncogenes
313:Functions
244:recessive
236:oncogenes
129:in 1969.
107:oncogenes
83:apoptosis
72:oncogenes
3646:Stathmin
3391:Cyclin E
3386:Cyclin D
3024:HER2/neu
2904:Receptor
2778:Research
2638:Blastoma
2455:oncology
2406:Archived
2349:23355908
2309:PLOS ONE
2285:15047927
2150:25557041
2098:24387338
2034:23210086
1929:23125015
1880:19361179
1872:16341240
1837:11420478
1788:29540752
1739:17613548
1708:11060332
1681:22154824
1673:12841864
1664:11160151
1622:11058615
1581:19601800
1546:25400280
1505:22711703
1464:42925807
1456:18097988
1421:30562755
1145:18712326
1137:14744434
951:Oncogene
930:See also
817:G1 phase
674:Two-Hit?
659:Examples
614:liposome
552:In vitro
451:(MSH2)).
366:hormones
252:dominant
248:oncogene
91:genetics
3636:c-Bcl-2
3444:Fanconi
3357:Nucleus
2788:History
2687:grading
2683:Staging
2648:Adenoma
2633:Sarcoma
2340:3552954
2317:Bibcode
2218:8841019
2141:4526158
2089:4032821
2025:3507026
1920:3536334
1828:1421942
1779:5852963
1361:9823898
1352:5395202
1331:Bibcode
1304:2144057
1284:Bibcode
1276:Science
1228:5279523
1196:Bibcode
925:DLD/NP1
867:SWI/SNF
821:S phase
631:capsule
622:muscles
610:plasmid
576:ligated
568:mutated
566:either
556:in vivo
544:vectors
537:vectors
533:viruses
485:histone
376:(APC)).
234:Unlike
101:History
54:, is a
3426:p14arf
3339:Maspin
3019:c-ErbB
2857:Ligand
2519:Cancer
2451:cancer
2447:tumors
2347:
2337:
2283:
2216:
2148:
2138:
2120:Cancer
2096:
2086:
2032:
2022:
2008:: 27.
1927:
1917:
1878:
1870:
1835:
1825:
1786:
1776:
1737:
1706:
1679:
1671:
1661:
1620:
1579:
1544:
1503:
1462:
1454:
1419:
1359:
1349:
1323:Nature
1302:
1226:
1219:389051
1216:
1143:
1135:
956:Cancer
908:, and
601:immune
560:tumors
395:, and
196:allele
174:, two
93:, and
64:cancer
50:), or
3641:Notch
3560:c-Myc
3553:c-Jun
3548:c-Fos
3464:BRCA2
3459:BRCA1
3323:c-Src
3280:c-Raf
3270:c-Ras
3196:c-Akt
3167:SMAD4
3162:SMAD2
3070:c-Kit
3041:c-Ret
3036:c-Met
3029:Her 3
2957:PTCH1
2771:Misc.
2657:Other
2597:Blood
1876:S2CID
1677:S2CID
1460:S2CID
1141:S2CID
976:BRCA1
918:BRCA2
902:YPEL3
870:is a
848:BCL2.
747:BRCA2
606:cells
584:tumor
521:viral
434:CADM1
150:genes
119:genes
3616:SDHD
3611:SDHB
3576:KLF6
3543:AP-1
3536:ONCO
3498:MDM2
3486:ONCO
3381:CDK4
3374:ONCO
3316:ONCO
3275:HRAS
3263:ONCO
3212:PTEN
3189:ONCO
3110:ONCO
3075:Flt3
3063:ONCO
3015:ErbB
3008:ONCO
2928:CDH1
2874:ONCO
2847:and
2803:Diet
2592:Skin
2587:Bone
2555:oral
2483:Cyst
2453:and
2345:PMID
2281:PMID
2214:PMID
2146:PMID
2094:PMID
2030:PMID
1925:PMID
1868:PMID
1833:PMID
1784:PMID
1735:PMID
1704:PMID
1669:PMID
1618:PMID
1577:PMID
1542:PMID
1501:PMID
1452:PMID
1417:PMID
1357:PMID
1300:PMID
1224:PMID
1133:PMID
1115:Cell
910:ST14
894:CD95
886:pVHL
851:BCL2
834:TP53
831:p53.
779:PTCH
668:Gene
546:and
492:and
466:and
464:TP53
447:and
353:and
317:The
216:loci
60:cell
56:gene
34:The
3569:TSP
3514:VHL
3507:TSP
3493:CBL
3452:TSP
3422:p16
3417:WT1
3412:pRb
3407:p53
3400:TSP
3332:TSP
3289:TSP
3234:TSP
3205:TSP
3155:TSP
3133:APC
3126:TSP
2979:TSP
2950:TSP
2921:TSP
2886:HGF
2695:TNM
2335:PMC
2325:doi
2273:doi
2204:doi
2136:PMC
2128:doi
2124:121
2084:PMC
2076:doi
2020:PMC
2010:doi
1915:PMC
1907:doi
1860:doi
1823:PMC
1815:doi
1811:234
1774:PMC
1766:doi
1727:doi
1659:PMC
1649:doi
1608:doi
1569:doi
1532:doi
1528:282
1491:doi
1444:doi
1407:doi
1347:PMC
1339:doi
1327:396
1292:doi
1280:249
1214:PMC
1204:doi
1123:doi
1119:116
981:p53
914:p16
906:ST7
898:ST5
890:APC
838:p53
825:E2F
813:RB1
805:pRb
788:No
770:No
763:NF1
754:Yes
738:Yes
731:APC
722:Yes
715:VHL
699:p53
690:Yes
643:DNA
612:or
580:p53
468:FAS
445:p53
441:DNA
408:p53
397:p14
393:p16
355:p16
351:pRB
307:p27
48:TSG
3663::
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