Información del artículo
Resumen
Los genes supresores tumorales están implicados en diversos procesos de división celular como la regulación de la expresión génica, control del ciclo celular, programación de la muerte celular y estabilidad del genoma. La pérdida de actividad de estos genes provoca la incapacidad de respuesta a los mecanismos de control que regulan la división celular, de modo que se produce una proliferación más o menos incontrolada de la célula lo cual conduce en ocasiones al desarrollo de neoplasias y a la evolución de las mismas hacia procesos tumorales más agresivos.
El gen p53 pertenece al grupo de genes implicados en el control del ciclo celular. Este gen tiene múltiples funciones ya que aparece implicado no sólo en el control del ciclo celular sino también en la integridad del ADN y la supervivencia de las células expuestas a agentes que dañan el ADN. La alteración del gen p53 confiere un riesgo muy elevado de desarrollar cáncer y la mutación del mismo es uno de los cambios genómicos más frecuentes en el cáncer humano.
Palabras Clave:
p53
mutación
apoptosis
gen supresor tumoral
Summary
Tumor suppressor genes are involved in several processes of cell division such as, transcriptional regulation, cell cycle control, programmed cell death and genome stability. Loss of activity of these genes causes the inability of response to the mechanisms of control that regulate cell division, so that an uncontrolled cell proliferation is caused which sometimes leads to the development of neoplasias.
p53 tumor suppressor gene is a multifactorial factor able to control cell cycle progression, DNA integrity and survival of the cells exposed to DNA damaging agents. p53 gene alteration confers a high risk of developing cancer and its mutation is one of the most frequent genetic changes in human neoplasia.
Keywords:
p53
mutation
apoptosis
tumor suppressor gene
Laburpena
Gene supresore tumoralek zatiketa zelularraren zenbait prozesutan parte hartzen dute, hala nola gene adierazpenaren erregulazioa, ziklo zelularraren kontrola, heriotza zelularraren programazioa eta genomaren egonkortasuna. Gene hauek beren jarduera gaitzeak zatiketa zelularra erregulatzen duten kontrol mekanismoei erantzuteko gaitasuna ezezetatzen du, eta ondorioz, zelularon ugaltze gutxiasko kontrolik gabea gertazen da; beraz, zenbaitetan neoplasiak garatzen dira eta neoplasia horiek agresiboagoak diren prozesu tumoral bihurtzen dira.
p53 genea ziklo zelularraren kontrolean parte hartzen duten geneen taldekoa da. Gene honek era askolako funtzioak ditu, ziklo zelularraren kontrolean agertzeaz gainera, ADNaren integritatean eta ADNa kaltetzen duten agenteen eraginaren mende dauden zelulen biziraupenean ere zeresanik baitu, p53 genea aldatzeak minbizia garatzeko arrisku oso handia dakar eta haren mutazioa giza minbiziaren aldaketa genomiko sarrienetako bat da.
Hitz Nagusiak:
p53
mutazioa
apoptosia
gene supresore tumorala
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Referencias bibliográficas
[1.]
Rosell R..
Molecular origins of human cancer.
Manual de oncología clinica y molecular, pp. 1-15
[4.]
Harris H..
The genetic analysis of malignancy.
J Cell Science, 4 (1986), pp. 431-444
[5.]
Brown M.A..
Tumor suppressor genes and human cancer.
Advances in Genetics, 36 (1997), pp. 45-135
[6.]
Lane D., Crawford L.V..
T antigen is bound to a host protein in SV40-transformed cells.
Nature, 278 (1979), pp. 261-263
[7.]
Linzer D.I., Levine A.J..
Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells an uninfected embryonal carcinoma cells.
Cell, 17 (1979), pp. 43-52
[8.]
Malkin D..
Germline p53 mutations and heritable cancer.
Annu Rev Genetics, 28 (1994), pp. 443-465
[9.]
Levine A.J., Momand J., Finlay C.A..
The p53 tumour suppressor gene.
Nature, 351 (1991), pp. 453-456
[11.]
Montenarh M..
Functional implications of the growth-suppressor/oncoprotein p53.
Int J Oncol, 1 (1992), pp. 37-45
[12.]
Hollstein M., Sidransky D., Vogelstein B., Harris C.C..
p53 mutations in human cancers.
Science, 253 (1991), pp. 49-53
[13.]
Roter V., Prokocimer M..
p53 and human malignancies.
Adv Cancer Res, 57 (1991), pp. 257-272
[15.]
Caron C., Fromentel C., Soussi T..
TP53 tumor suppressor gene: a model for investigating human mutagenesis.
Genes Chromosome Cancer, 4 (1992), pp. 1-15
[16.]
Dutta A., Ruppert J.M., Aster J.C., Winchester E..
Inhibition of DNA replication factor RPA by p53.
Nature, 365 (1993), pp. 79-82
[17.]
Pietenpol J.A., Vogelstein B..
No room at the p53 inn.
Nature, 365 (1993), pp. 17-18
[18.]
Levine A.J..
p53, the cellular gatekeeper for growth and division.
Cell, 88 (1995), pp. 323-331
[19.]
Cross S.M., Sanchez C.A., Morgan C.A., Schimke M.K., Ramel S., Idzerda R.L., Raskind V.H., Reid B.J..
A p53-dependent mouse spindle checkpoint.
Science, 267 (1995), pp. 1353-1356
[22.]
Maltzman W., Czyzyk L..
UV irradiations stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells.
Mol Cell Biol, 4 (1984), pp. 1689-1694
[23.]
Kastan M.B., Onyekwere O., Sidransky D., Vogelstein B., Craig R.W..
Participation of p53 protein in the cellular response to DNA damage.
Cancer Res, 51 (1991), pp. 6304-6311
[24.]
Lu X., Lane D.P..
Differential induction of transcriptionally active p53 following UV or ionising radiation: Defects in chromosome instability syndromes.
Cell, 75 (1993), pp. 765-778
[25.]
Fritsche C., Haessler C., Brandner G..
Induction of nuclear accumulation of the tumor suppressor protein p53 by DNA-damaging agents.
Oncogene, 8 (1993), pp. 307-318
[26.]
Harris C.C., Holstein M..
Clinical implications of the p53 tumor-suppressor gene.
N Engl J Med, 329 (1993), pp. 1318-1327
[27.]
Harris C.C..
The p53 tumour suppressor gene: at the crossroads of molecular carcinogenesis and risk assessment.
Science, 262 (1993), pp. 1980-1981
[28.]
Momand J., Zambetti G.P., Olson D.C., George D., Levine A.L..
The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation.
Cell, 69 (1992), pp. 1237-1245
[29.]
Oliner J.D., Pietenpol J.A., Thiagalingam S., Gyuris J., Kinzler K.W., Vogelstein B..
Oncoprotein MDM2 conceals the activation domain of tumor suppressor p53.
Nature, 362 (1993), pp. 857-860
[30.]
Sionov R.V., Haupt Y..
The cellular response to p53: the decision between life and death.
Oncogene, 18 (1998), pp. 6145-6157
[31.]
Hansen R., Oren M..
p53; from inductive signal to cellular effect.
Curr Op Genet & Dev, 7 (1997), pp. 46-51
[32.]
Mowat M.A., Cheng A., Kimura N., Bernstein A., Benchimol S..
Rearrangements of the cellular p53 gene in erythroleukaemia cells transformed by friend virus.
Nature, 314 (1985), pp. 633-636
[33.]
Prokocimer M., Shaklai M., Bassat H.B., Wolf D., Goldfinger N., Rotter V..
Expression of p53 in human leukemia and lymphoma.
Blood, 68 (1986), pp. 113-118
[34.]
Masuda H., Miller C., Koeffler H., Battifora A., Cline M.J..
Rearrangement of the p53 gene in human osteogenic sarcomas.
Proc Natl Acad Sci USA, 84 (1987), pp. 7716-7726
[35.]
Ahuja H., Bar-Eli M., Advani S.H., Benchimol S., Cline M.J..
Alterations in the p53 gene and the clonal evolution of the blast crisis of chronic myelocytic leukemia.
Proc Natl Acad Sci. USA, 86 (1989), pp. 6783-6787
[36.]
Takahashi T., Nau M.M., Chiba I., Birrer M.J., Rosenberg R.K., Vinocour M., Levitt M., Pass H., Gazdar A.F., Minna J.D..
P53: a frequent target for genetic abnormalities in lung cancer.
Science, 246 (1989), pp. 491-494
[37.]
Greenblatt M.S., Bennet W.P., Hollstein M., Harris C.C..
Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis.
Cancer Res, 54 (1994), pp. 48554878
[38.]
Soussi T..
The p53 tumour suppresor gene: a model for molecular epidemiology of human cancer.
Mol Med Today, 2 (1996), pp. 32-37
[39.]
Harris C.C..
The 1995 Walter Hubert Lecturemolecular epidemiology of human cancer: insights from the mutational analysis of the p53 tumor-suppressor gene.
Br J Cancer, 73 (1996), pp. 261-269
[40.]
Benito de las Heras M..
Implicaciones de los oncogenes en el cáncer de colon.
Rev Cancer, 6 (1992), pp. 156-159
[41.]
Hupp T.R., Lane D.P..
Allosteric activation of latent p53 tretramers.
Curr Biol, 4 (1994), pp. 865-875
[42.]
Hainault P., Hall A., Milner J..
Analysis of p53 quaternary structure in relation to sequencespecific DNA binding.
Oncogene, 9 (1994), pp. 299303
[43.]
Wang Y., Schwedes J.F., Parks D., Mann K., Tegtmeyer P..
Interaction of p53 with its consensus DNA binding site.
Mol Cell Biol, 15 (1995), pp. 2157-2165
[44.]
Davidoff A.M., Humphrey P.A., Iglehart J.D., Marks J.R..
Genetic basis for p53 overexpression in human breast cancer.
Proc Natl Acad Sci USA, 88 (1991), pp. 5006-5010
[45.]
Hainault S., Soussi T., Shomer B., Hollstein M., Greenblat M., Hovig E., Harris C.C., Montesano R..
Database of p53 gene somatic mutations in human tumors and cell lines: updated compilation and future prospects.
Nucleic Acids Res, 25 (1997), pp. 151-157
[46.]
Gannon J.V., Greaves R., Iggo R., Lane D.P..
Activating mutations in p53 produce a common conformational effect: a monoclonal antibody specific for the mutant form.
EMBO J, 9 (1990), pp. 1595-1602
[47.]
Bartek J., Bartkova J., Vogtësek B..
Aberrant expression of the p53 oncoprotein is a common feature of a wide spectrum of human malignancies.
Oncogene, 6 (1991), pp. 1699-1703
[49.]
Ory K., Legros Y., Auguin C., Soussi T..
Analysis of the most representative tumour-derived p53 mutants reveals that changes in protein conformation are not correlated with loss of transactivation or inhibition of cell proliferation.
EMBO J, 13 (1994), pp. 3496-3504
[50.]
Forrester K., Lupold S.E., Ott V.L., Chay C.H., Band V., Wang X.W., Harris C.C..
Effects of the p53 mutants reveals that changes in protein conformation are not correlated with loss of transactivation or inhibition of cell proliferation.
EMBO J, 13 (1994), pp. 3496-3504
[50.]
Forrester K., Lupold S.E., Ott V.L., Chay C.H., Band V., Wang X.W., Harris C.C..
Effects of the p53 mutants on wild-type p53 mediated transactivation are cell type dependent.
Oncogene, 10 (1995), pp. 2011-2103
[51.]
Rolley N., Butcher S., Milner J..
Specific DNA binding by different classes of human p53 mutants.
Oncogene, 11 (1995), pp. 763-770
[52.]
Greenblatt M.S., Grollman A.P., Harris C.C..
Deletions and insertions in the p53 tumor suppressor gene in human cancers: confirmation of the DNA polymerase slippage/misalignment model.
Cancer Res, 56 (1996), pp. 2130-2136
[53.]
Harris C.C..
p53 tumor suppressor gene: from the basic research laboratory to the clinic an abridged historical perspective.
Carcinogenesis, 17 (1996), pp. 1187-1198
[54.]
Diamandis E.F..
Clinical applications of the p53 tumor suppressor gene.
Clinica Chimica Acta, 237 (1995), pp. 79-90
[55.]
De Mendoza G., Barberá G..
P53: factores que modulan su actividad reguladora.
Rev Diagn Biol, 48 (1999), pp. 51-61
[56.]
El-Dairy W.S., Tokino T., Velculescu V.E., Levy D.B., Parsons R., Trent J.M., Lin D., Mercer E., Kinzler K.W., Vogelstein B..
WAF1, a potential mediator of p53 tumor suppression.
Cell, 75 (1993), pp. 817-825
[57.]
Harper J.W., Adami G.R., Wei N., Keyomarsi K., Elledge S.J..
The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.
Cell, 75 (1993), pp. 805-816
[58.]
Harris C.C., Hollstein M..
Clinical implications of the p53 tumor suppressor gene.
N Engl J Med, 329 (1993), pp. 1318-1326
[59.]
Lehman T.A., Bennett W.P., Metcalf R.A., Welsh J.A., Ecker J., Modali R.V., Ullrich S., Romano J.W., Appella E., Testa J.R..
p53 mutations ras mutations, and p53 heat shock 70 protein complexes in human lung carcinoma cell lines.
Cancer Res, 51 (1991), pp. 4090-4096
[60.]
Oliner J.D., Kinzler K.W., Meltzer P.S., Geore D.L., Volgestein B..
Amplification of a gene encoding a p53 associated protein in human sarcomas.
Nature, 358 (1992), pp. 80-83
[61.]
Sidransky D..
Nucleic acid-based methods for the detection of cancer.
Science, 278 (1998), pp. 1054-1058
[62.]
DeRisi J., Penland L., Brown P.O., Bittner M.L., Meltzer P.S., Ray M., Chen Y., Su Y.A., Trent J.M..
Use of a cDNA microarray to analyse gene expression patterns in human cancer.
Nature Genet, 14 (1992), pp. 457-460
[63.]
Zhang L., Zou W., Velculescu V.E., Kern S.E., Hruben R.H., Hamilton S.R., Vogelstein B., Kinzler W..
Gene expression profiles in normal and cancer cells.
Science, 276 (1997), pp. 1268-1272
[64.]
Feitelson M.A., Zhu M., Duan L.X., London W.T..
Hepatitis B X antigen and p53 are associated in vitro and in liver tissues from patients with primary hepatocellular carcinoma.
Oncogene, 8 (1993), pp. 1109-1117
[65.]
Szekely L., Selinova G., Magnusson K.P., Klein G., Wiman K.G..
EBNA-5 an Eipstein Barr virus encoded nuclear antigen, binds to the retinoblastoma and p53 proteins.
Proc Natl Acad Sci USA, 90 (1993), pp. 5455-5459
[66.]
Dobner T., Horikoshi N., Rubenwolf S., Shenk T..
Blockage by adenovirus E4orf6 of transcriptional activation by the p53 tumor suppressor.
Science, 272 (1996), pp. 1470-1473
[67.]
Khine K., Smith D.R., Goh H.S..
High frequency of allelic deletion on chromosome 17p in advanced colorectal cancer.
Cancer, 73 (1994), pp. 28-35
[68.]
Kohler M.F., Marks J.R., Wiseman R.W., Jacobs I.J., Davidoff A.M., Clarke-Pearson D.L., Soper J.T., Bast R.C. Jr, Berchuck A..
Spectrum of mutation and frequency of allelic deletion of the p53 gene in ovarian cancer.
J Natl Cancer Inst, 85 (1993), pp. 1513-1519
[69.]
Jego N., Thomas G., Mahemil R..
Short direct repeats flanking deletions, and duplicating insertions in p53 gene in human cancers.
Oncogene, 8 (1993), pp. 209-213
[70.]
Davidoff A.M., Humphrey P.A., Iglehart J.D., Marks J.R..
Genetic basis for p53 overexpression in human breast cancer.
Proc Natl Acad Sci USA, 88 (1991), pp. 5006-5010
[71.]
Chang F., Syrjanen S., Kurvinen K., Syrjanen K..
The p53 tumor suppressor gene as a common cellular target in human carcinogenesis.
Am J Gastroenterol, 88 (1993), pp. 174-186
[72.]
Chang F., Syrjanen S., Tervahauta A., Syrjanen K..
Tumorigenesis associated with the p53 tumor suppressor gene.
Br J Cancer, 68 (1993), pp. 653-661
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