From Fly Wings to Targeted Cancer Therapies: A Centennial for Notch Signaling
2014; Cell Press; Volume: 25; Issue: 3 Linguagem: Inglês
10.1016/j.ccr.2014.02.018
ISSN1878-3686
AutoresPanagiotis Ntziachristos, Jing Lim, Julien Sage, Iannis Aifantis,
Tópico(s)Histone Deacetylase Inhibitors Research
ResumoSince Notch phenotypes in Drosophila melanogaster were first identified 100 years ago, Notch signaling has been extensively characterized as a regulator of cell-fate decisions in a variety of organisms and tissues. However, in the past 20 years, accumulating evidence has linked alterations in the Notch pathway to tumorigenesis. In this review, we discuss the protumorigenic and tumor-suppressive functions of Notch signaling, and dissect the molecular mechanisms that underlie these functions in hematopoietic cancers and solid tumors. Finally, we link these mechanisms and observations to possible therapeutic strategies targeting the Notch pathway in human cancers. Since Notch phenotypes in Drosophila melanogaster were first identified 100 years ago, Notch signaling has been extensively characterized as a regulator of cell-fate decisions in a variety of organisms and tissues. However, in the past 20 years, accumulating evidence has linked alterations in the Notch pathway to tumorigenesis. In this review, we discuss the protumorigenic and tumor-suppressive functions of Notch signaling, and dissect the molecular mechanisms that underlie these functions in hematopoietic cancers and solid tumors. Finally, we link these mechanisms and observations to possible therapeutic strategies targeting the Notch pathway in human cancers. This year will be the centennial of the discovery of a signaling pathway that has fascinated developmental, molecular, and cancer biologists around the world. Mutant Notch phenotypes in the fly wing were characterized by John S. Dexter 100 years ago (Dexter, 1914Dexter J.S. The analysis of a case of continuous variation in Drosophila by a study of its linkage relationships.Am. Nat. 1914; 48: 712-758Crossref Google Scholar), and, rapidly thereafter, Thomas Hunt Morgan identified the mutant alleles (Morgan, 1917Morgan T. The theory of the gene.Am. Nat. 1917; 51: 513-544Crossref Google Scholar). Almost seven decades later, after the molecular biology revolution, Spyros Artavanis-Tsakonas and Michael Young cloned the Notch receptor and attributed the wing-notching phenotype to gene haploinsufficiency (Kidd et al., 1986Kidd S. Kelley M.R. Young M.W. Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors.Mol. Cell. Biol. 1986; 6: 3094-3108Crossref PubMed Google Scholar, Wharton et al., 1985Wharton K.A. Johansen K.M. Xu T. Artavanis-Tsakonas S. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats.Cell. 1985; 43: 567-581Abstract Full Text PDF PubMed Scopus (357) Google Scholar). These studies brought about a revolution in a large number of fields, including developmental and stem cell biology, neuroscience, and (related to this review) cancer biology (Fortini et al., 1993Fortini M.E. Rebay I. Caron L.A. Artavanis-Tsakonas S. An activated Notch receptor blocks cell-fate commitment in the developing Drosophila eye.Nature. 1993; 365: 555-557Crossref PubMed Scopus (215) Google Scholar). Indeed, in the early 1990s, gain-of-function mutations of the pathway were identified in cancer (Ellisen et al., 1991Ellisen L.W. Bird J. West D.C. Soreng A.L. Reynolds T.C. Smith S.D. Sklar J. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.Cell. 1991; 66: 649-661Abstract Full Text PDF PubMed Google Scholar, Gallahan and Callahan, 1997Gallahan D. Callahan R. The mouse mammary tumor associated gene INT3 is a unique member of the NOTCH gene family (NOTCH4).Oncogene. 1997; 14: 1883-1890Crossref PubMed Google Scholar, Gallahan et al., 1987Gallahan D. Kozak C. Callahan R. A new common integration region (int-3) for mouse mammary tumor virus on mouse chromosome 17.J. Virol. 1987; 61: 218-220Crossref PubMed Google Scholar, Jhappan et al., 1992Jhappan C. Gallahan D. Stahle C. Chu E. Smith G.H. Merlino G. Callahan R. Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands.Genes Dev. 1992; 6: 345-355Crossref PubMed Google Scholar). A deluge of reports followed, cementing the role of Notch signaling as oncogenic but also tumor suppressive, depending on the context. In this review, we attempt to provide a detailed characterization of Notch functions in both solid and hematopoietic cancers. In addition, we discuss the molecular mechanisms that underlie such functions, as well as approaches to target Notch signaling in human cancers. There are four Notch receptors (named Notch1–Notch4) in mammals. Notch1 and Notch2 each have 36 epidermal growth factor (EGF)-like repeats, while Notch3 and Notch4 have 34 and 29 repeats, respectively, which affects their affinity for corresponding ligands (Haines and Irvine, 2003Haines N. Irvine K.D. Glycosylation regulates Notch signalling.Nat. Rev. Mol. Cell Biol. 2003; 4: 786-797Crossref PubMed Scopus (322) Google Scholar, Okajima and Irvine, 2002Okajima T. Irvine K.D. Regulation of notch signaling by o-linked fucose.Cell. 2002; 111: 893-904Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, Rebay et al., 1991Rebay I. Fleming R.J. Fehon R.G. Cherbas L. Cherbas P. Artavanis-Tsakonas S. Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor.Cell. 1991; 67: 687-699Abstract Full Text PDF PubMed Google Scholar; Figure 1). Notch receptors are single-pass type I transmembrane molecules coded by a single precursor that becomes a noncovalently linked heterodimer. This heterodimer consists of an N-terminal extracellular (NEC) fragment and a C-terminal transmembrane-intracellular subunit (NTM) as a result of cleavage by a furin-like protease in the trans-Golgi network (Blaumueller et al., 1997Blaumueller C.M. Qi H. Zagouras P. Artavanis-Tsakonas S. Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane.Cell. 1997; 90: 281-291Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar; Figures 1 and 2). The Notch pathway is normally activated upon interactions with ligands such as Delta-like and Jagged, which are also transmembrane proteins containing EGF-like repeats. In mammals, there are three Delta-like ligands (Dll1, Dll3, and Dll4) and two Jagged ligands (Jag1 and Jag2). The Notch pathway is activated in a strictly controlled fashion: ADAM10/17 metalloproteases cause an S2 cleavage in the receptor, followed by a third cleavage (S3 cleavage) mediated by the presenilin-γ-secretase complex, which is composed of presenilin 1 (PSEN1), PSEN2, nicastrin (NCSTN), presenilin enhancer 2 (PEN2), and anterior pharynx-defective 1 (APH1) (Shah et al., 2005Shah S. Lee S.F. Tabuchi K. Hao Y.H. Yu C. LaPlant Q. Ball H. Dann 3rd, C.E. Südhof T. Yu G. Nicastrin functions as a gamma-secretase-substrate receptor.Cell. 2005; 122: 435-447Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar). This series of events releases the intracellular portion of the Notch receptor (termed ICN), which then translocates into the nucleus to mediate target gene activation (De Strooper et al., 1999De Strooper B. Annaert W. Cupers P. Saftig P. Craessaerts K. Mumm J.S. Schroeter E.H. Schrijvers V. Wolfe M.S. Ray W.J. et al.A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.Nature. 1999; 398: 518-522Crossref PubMed Scopus (1363) Google Scholar, Schroeter et al., 1998Schroeter E.H. Kisslinger J.A. Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.Nature. 1998; 393: 382-386Crossref PubMed Scopus (1059) Google Scholar). Notch-ICN is a transcriptional activator (Bray, 2006Bray S.J. Notch signalling: a simple pathway becomes complex.Nat. Rev. Mol. Cell Biol. 2006; 7: 678-689Crossref PubMed Scopus (996) Google Scholar) consisting of ankyrin repeats, a RAM (RBP-Jκ associated molecule) domain, a transactivation domain (TAD), a nuclear localization signal (NLS), and a PEST domain that regulates protein stability (Figures 1 and 2). Notch ligands are also cleaved by γ-secretase and ADAM metalloprotease complexes, thus providing an additional level of regulation of the pathway (LaVoie and Selkoe, 2003LaVoie M.J. Selkoe D.J. The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments.J. Biol. Chem. 2003; 278: 34427-34437Crossref PubMed Scopus (211) Google Scholar, Six et al., 2003Six E. Ndiaye D. Laabi Y. Brou C. Gupta-Rossi N. Israel A. Logeat F. The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase.Proc. Natl. Acad. Sci. USA. 2003; 100: 7638-7643Crossref PubMed Scopus (167) Google Scholar). Despite the overall similarities between the receptors, the differences in the ligand-binding extracellular domains and the transactivation intracellular domains lead to distinct ligand affinities and capacities to activate downstream transcription.Figure 2Overview of the Notch Signaling PathwayShow full captionA visual description of the signaling cascade is shown for the signal-receiving cell (i.e., the cell expressing the Notch receptor). The pathway inhibitors used include antibodies against NOTCH receptors and DLL ligands, GSIs, and small peptides that inhibit formation of the transcriptional complex. Antibody-based treatments are shown in purple, GSI compounds are in pink, and peptide-based drugs are in red. Potential epigenetic inhibitors (in green) can include BRD inhibitors such as JQ1. HDAC, histone deacetylase; ICN1, intracellular part of NOTCH1; LSD1, lysine-specific demethylase 1; SMRT, Silencing-Mediator for Retinoid/Thyroid hormone receptors; GSK3β, glycogen synthase kinase 3 beta; DNMAML1, dominant-negative MAML1.View Large Image Figure ViewerDownload Hi-res image Download (PPT) A visual description of the signaling cascade is shown for the signal-receiving cell (i.e., the cell expressing the Notch receptor). The pathway inhibitors used include antibodies against NOTCH receptors and DLL ligands, GSIs, and small peptides that inhibit formation of the transcriptional complex. Antibody-based treatments are shown in purple, GSI compounds are in pink, and peptide-based drugs are in red. Potential epigenetic inhibitors (in green) can include BRD inhibitors such as JQ1. HDAC, histone deacetylase; ICN1, intracellular part of NOTCH1; LSD1, lysine-specific demethylase 1; SMRT, Silencing-Mediator for Retinoid/Thyroid hormone receptors; GSK3β, glycogen synthase kinase 3 beta; DNMAML1, dominant-negative MAML1. In the nucleus, Notch binds to initially inactive CBF1-Su(H)-LAG1 (CSL) (aka RBP-Jκ)-containing complexes and mediates their conversion to a transcriptional activator followed by the recruitment of the coactivator protein mastermind-like 1 (MAML1) (Figure 2; Nam et al., 2006Nam Y. Sliz P. Song L. Aster J.C. Blacklow S.C. Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes.Cell. 2006; 124: 973-983Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar, Wilson and Kovall, 2006Wilson J.J. Kovall R.A. Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA.Cell. 2006; 124: 985-996Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, Wu et al., 2000Wu L. Aster J.C. Blacklow S.C. Lake R. Artavanis-Tsakonas S. Griffin J.D. MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors.Nat. Genet. 2000; 26: 484-489Crossref PubMed Scopus (313) Google Scholar). The ankyrin repeats seem to play an important role in MAML1 recruitment. The list of target genes regulated by Notch is very much dependent on cell type and can include genes whose products are involved in fundamental aspects of cell biology, such as cell-cycle regulation (Joshi et al., 2009Joshi I. Minter L.M. Telfer J. Demarest R.M. Capobianco A.J. Aster J.C. Sicinski P. Fauq A. Golde T.E. Osborne B.A. Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases.Blood. 2009; 113: 1689-1698Crossref PubMed Scopus (61) Google Scholar, Lewis et al., 2007Lewis H.D. Leveridge M. Strack P.R. Haldon C.D. O'Neil J. Kim H. Madin A. Hannam J.C. Look A.T. Kohl N. et al.Apoptosis in T cell acute lymphoblastic leukemia cells after cell cycle arrest induced by pharmacological inhibition of notch signaling.Chem. Biol. 2007; 14: 209-219Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar), cellular differentiation, and metabolism (Palomero et al., 2006Palomero T. Lim W.K. Odom D.T. Sulis M.L. Real P.J. Margolin A. Barnes K.C. O'Neil J. Neuberg D. Weng A.P. et al.NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.Proc. Natl. Acad. Sci. USA. 2006; 103: 18261-18266Crossref PubMed Scopus (315) Google Scholar). Common targets of the pathway include the HES and HEY families of transcription repressors (Iso et al., 2001aIso T. Sartorelli V. Chung G. Shichinohe T. Kedes L. Hamamori Y. HERP, a new primary target of Notch regulated by ligand binding.Mol. Cell. Biol. 2001; 21: 6071-6079Crossref PubMed Scopus (128) Google Scholar, Iso et al., 2001bIso T. Sartorelli V. Poizat C. Iezzi S. Wu H.Y. Chung G. Kedes L. Hamamori Y. HERP, a novel heterodimer partner of HES/E(spl) in Notch signaling.Mol. Cell. Biol. 2001; 21: 6080-6089Crossref PubMed Scopus (129) Google Scholar, Jarriault et al., 1995Jarriault S. Brou C. Logeat F. Schroeter E.H. Kopan R. Israel A. Signalling downstream of activated mammalian Notch.Nature. 1995; 377: 355-358Crossref PubMed Google Scholar), as well as the MYC transcription factor (Palomero et al., 2006Palomero T. Lim W.K. Odom D.T. Sulis M.L. Real P.J. Margolin A. Barnes K.C. O'Neil J. Neuberg D. Weng A.P. et al.NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.Proc. Natl. Acad. Sci. USA. 2006; 103: 18261-18266Crossref PubMed Scopus (315) Google Scholar, Sharma et al., 2006Sharma V.M. Calvo J.A. Draheim K.M. Cunningham L.A. Hermance N. Beverly L. Krishnamoorthy V. Bhasin M. Capobianco A.J. Kelliher M.A. Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc.Mol. Cell. Biol. 2006; 26: 8022-8031Crossref PubMed Scopus (132) Google Scholar, Weng et al., 2006Weng A.P. Millholland J.M. Yashiro-Ohtani Y. Arcangeli M.L. Lau A. Wai C. Del Bianco C. Rodriguez C.G. Sai H. Tobias J. et al.c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma.Genes Dev. 2006; 20: 2096-2109Crossref PubMed Scopus (358) Google Scholar). The binding of Notch on DNA appears to be a rapid and dynamic process controlled by the kinase CDK8 and the ubiquitin ligase Fbxw7, followed by phosphorylation, ubiquitination, and proteasomal degradation of Notch (Fryer et al., 2004Fryer C.J. White J.B. Jones K.A. Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover.Mol. Cell. 2004; 16: 509-520Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, Mukherjee et al., 2005Mukherjee A. Veraksa A. Bauer A. Rosse C. Camonis J. Artavanis-Tsakonas S. Regulation of Notch signalling by non-visual beta-arrestin.Nat. Cell Biol. 2005; 7: 1191-1201Crossref PubMed Scopus (7) Google Scholar, O'Neil et al., 2007O'Neil J. Grim J. Strack P. Rao S. Tibbitts D. Winter C. Hardwick J. Welcker M. Meijerink J.P. Pieters R. et al.FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.J. Exp. Med. 2007; 204: 1813-1824Crossref PubMed Scopus (249) Google Scholar, Thompson et al., 2007Thompson B.J. Buonamici S. Sulis M.L. Palomero T. Vilimas T. Basso G. Ferrando A. Aifantis I. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia.J. Exp. Med. 2007; 204: 1825-1835Crossref PubMed Scopus (202) Google Scholar), which shuts off the pathway (Figure 2). Various tools have been developed to study the transcriptional activity of the pathway, such as chromatin immunoprecipitation sequencing (ChIP-seq) and ChIP-chip to map Notch1 binding on the genome (Castel et al., 2013Castel D. Mourikis P. Bartels S.J. Brinkman A.B. Tajbakhsh S. Stunnenberg H.G. Dynamic binding of RBPJ is determined by Notch signaling status.Genes Dev. 2013; 27: 1059-1071Crossref PubMed Scopus (14) Google Scholar, Ntziachristos et al., 2012Ntziachristos P. Tsirigos A. Van Vlierberghe P. Nedjic J. Trimarchi T. Flaherty M.S. Ferres-Marco D. da Ros V. Tang Z. Siegle J. et al.Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia.Nat. Med. 2012; 18: 298-301Crossref PubMed Scopus (76) Google Scholar, Palomero et al., 2006Palomero T. Lim W.K. Odom D.T. Sulis M.L. Real P.J. Margolin A. Barnes K.C. O'Neil J. Neuberg D. Weng A.P. et al.NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.Proc. Natl. Acad. Sci. USA. 2006; 103: 18261-18266Crossref PubMed Scopus (315) Google Scholar, Wang et al., 2011aWang H. Zou J. Zhao B. Johannsen E. Ashworth T. Wong H. Pear W.S. Schug J. Blacklow S.C. Arnett K.L. et al.Genome-wide analysis reveals conserved and divergent features of Notch1/RBPJ binding in human and murine T-lymphoblastic leukemia cells.Proc. Natl. Acad. Sci. USA. 2011; 108: 14908-14913Crossref PubMed Scopus (52) Google Scholar), and mouse models that allow efficient tracing of receptor cleavage/activity in many different tissues (Hansson et al., 2006Hansson E.M. Teixeira A.I. Gustafsson M.V. Dohda T. Chapman G. Meletis K. Muhr J. Lendahl U. Recording Notch signaling in real time.Dev. Neurosci. 2006; 28: 118-127Crossref PubMed Scopus (19) Google Scholar, Liu et al., 2011Liu Z. Turkoz A. Jackson E.N. Corbo J.C. Engelbach J.A. Garbow J.R. Piwnica-Worms D.R. Kopan R. Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice.J. Clin. Invest. 2011; 121: 800-808Crossref PubMed Scopus (57) Google Scholar, Mizutani et al., 2007Mizutani K. Yoon K. Dang L. Tokunaga A. Gaiano N. Differential Notch signalling distinguishes neural stem cells from intermediate progenitors.Nature. 2007; 449: 351-355Crossref PubMed Scopus (243) Google Scholar, Souilhol et al., 2006Souilhol C. Cormier S. Monet M. Vandormael-Pournin S. Joutel A. Babinet C. Cohen-Tannoudji M. Nas transgenic mouse line allows visualization of Notch pathway activity in vivo.Genesis. 2006; 44: 277-286Crossref PubMed Scopus (22) Google Scholar). Recently, the group of Artavanis-Tsakonas (Fre et al., 2011Fre S. Hannezo E. Sale S. Huyghe M. Lafkas D. Kissel H. Louvi A. Greve J. Louvard D. Artavanis-Tsakonas S. Notch lineages and activity in intestinal stem cells determined by a new set of knock-in mice.PLoS ONE. 2011; 6: e25785Crossref PubMed Scopus (27) Google Scholar, Šale et al., 2013Šale S. Lafkas D. Artavanis-Tsakonas S. Notch2 genetic fate mapping reveals two previously unrecognized mammary epithelial lineages.Nat. Cell Biol. 2013; 15: 451-460Crossref PubMed Scopus (19) Google Scholar) and members of our laboratory (Oh et al., 2013Oh P. Lobry C. Gao J. Tikhonova A. Loizou E. Manent J. van Handel B. Ibrahim S. Greve J. Mikkola H. et al.In vivo mapping of notch pathway activity in normal and stress hematopoiesis.Cell Stem Cell. 2013; 13: 190-204Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar) traced Notch pathway activity in vivo by using reporter systems for Notch receptor expression and Hes1 activity by coupling them to fluorescent proteins (Figure 3). Since there are several unanswered questions regarding Notch ligand expression, even under physiological conditions, an exciting next step could involve the development of fluorescent tools to probe ligand expression together with pathway activation in real time within a living organism. The Notch pathway is genetically altered in a large number of hematopoietic and solid tumors (Figure 1). Intriguingly, these alterations can lead to either activation or repression of the pathway depending on the context and the activation status of other potentially oncogenic pathways (Table 1; Figure 4). Interestingly, it appears that there are multiple and distinct modes of aberrant regulation of the pathway and its targets in cancer. They include activating and inactivating mutations, receptor/ligand overexpression, epigenetic regulation, and effects of posttranslational modifications, most notably receptor and ligand fucosylation (especially O-fucosylation) (Haines and Irvine, 2003Haines N. Irvine K.D. Glycosylation regulates Notch signalling.Nat. Rev. Mol. Cell Biol. 2003; 4: 786-797Crossref PubMed Scopus (322) Google Scholar, Lei et al., 2003Lei L. Xu A. Panin V.M. Irvine K.D. An O-fucose site in the ligand binding domain inhibits Notch activation.Development. 2003; 130: 6411-6421Crossref PubMed Scopus (59) Google Scholar, Okajima et al., 2003Okajima T. Xu A. Irvine K.D. Modulation of notch-ligand binding by protein O-fucosyltransferase 1 and fringe.J. Biol. Chem. 2003; 278: 42340-42345Crossref PubMed Scopus (120) Google Scholar) and ubiquitination (Fryer et al., 2004Fryer C.J. White J.B. Jones K.A. Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover.Mol. Cell. 2004; 16: 509-520Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, Thompson et al., 2007Thompson B.J. Buonamici S. Sulis M.L. Palomero T. Vilimas T. Basso G. Ferrando A. Aifantis I. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia.J. Exp. Med. 2007; 204: 1825-1835Crossref PubMed Scopus (202) Google Scholar). We initially discuss T cell acute lymphoblastic leukemia (T-ALL), a disease in which Notch has a well-characterized oncogenic role. Subsequently, we present several other cases of hematopoietic and solid tumors in which Notch has tumor-suppressive or oncogenic roles, along with its potential mechanisms of action and partners.Table 1Oncogenic and Tumor-Suppressive Roles of Notch Signaling in Human CancersTumor TypeOncogene or Tumor SuppressorMutations (%) and Noteworthy ObservationsReferencesT cell acute lymphoblastic leukemia (T-ALL)oncogene50%–60% NOTCH1, 30% FBXW7Malyukova et al., 2007Malyukova A. Dohda T. von der Lehr N. Akhoondi S. Corcoran M. Heyman M. Spruck C. Grandér D. Lendahl U. Sangfelt O. The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling.Cancer Res. 2007; 67: 5611-5616Crossref PubMed Scopus (94) Google Scholar, Weng et al., 2004Weng A.P. Ferrando A.A. Lee W. Morris 4th, J.P. Silverman L.B. Sanchez-Irizarry C. Blacklow S.C. Look A.T. Aster J.C. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.Science. 2004; 306: 269-271Crossref PubMed Scopus (1148) Google Scholarrole in cancer initiation and maintenanceChronic lymphocytic leukemia (CLL)oncogene5%–12% NOTCH1Fabbri et al., 2011Fabbri G. Rasi S. Rossi D. Trifonov V. Khiabanian H. Ma J. Grunn A. Fangazio M. Capello D. Monti S. et al.Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation.J. Exp. Med. 2011; 208: 1389-1401Crossref PubMed Scopus (182) Google Scholar, Puente et al., 2011Puente X.S. Pinyol M. Quesada V. Conde L. Ordóñez G.R. Villamor N. Escaramis G. Jares P. Beà S. González-Díaz M. et al.Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia.Nature. 2011; 475: 101-105Crossref PubMed Scopus (425) Google Scholarrole in cancer initiation and survivalMelanomaoncogenic∼50% NOTCH1 overexpression in human samplesBalint et al., 2005Balint K. Xiao M. Pinnix C.C. Soma A. Veres I. Juhasz I. Brown E.J. Capobianco A.J. Herlyn M. Liu Z.J. Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression.J. Clin. Invest. 2005; 115: 3166-3176Crossref PubMed Scopus (170) Google Scholar, Bedogni et al., 2008Bedogni B. Warneke J.A. Nickoloff B.J. Giaccia A.J. Powell M.B. Notch1 is an effector of Akt and hypoxia in melanoma development.J. Clin. Invest. 2008; 118: 3660-3670Crossref PubMed Scopus (102) Google Scholarpossible role in metastasisCholangiocarcinoma (CCC)oncogenic35% FBXW7Akhoondi et al., 2007Akhoondi S. Sun D. von der Lehr N. Apostolidou S. Klotz K. Maljukova A. Cepeda D. Fiegl H. Dafou D. Marth C. et al.FBXW7/hCDC4 is a general tumor suppressor in human cancer.Cancer Res. 2007; 67: 9006-9012Crossref PubMed Scopus (131) Google Scholar, Zender et al., 2013Zender S. Nickeleit I. Wuestefeld T. Sörensen I. Dauch D. Bozko P. El-Khatib M. Geffers R. Bektas H. Manns M.P. et al.A critical role for notch signaling in the formation of cholangiocellular carcinomas.Cancer Cell. 2013; 23: 784-795Abstract Full Text Full Text PDF PubMed Scopus (14) Google ScholarNotch1 promotes tumor initiation and maintenanceColorectal canceroncogenic8%–9% FBXW7Miyaki et al., 2009Miyaki M. Yamaguchi T. Iijima T. Takahashi K. Matsumoto H. Mori T. Somatic mutations of the CDC4 (FBXW7) gene in hereditary colorectal tumors.Oncology. 2009; 76: 430-434Crossref PubMed Scopus (10) Google Scholar; Akhoondi et al., 2007Akhoondi S. Sun D. von der Lehr N. Apostolidou S. Klotz K. Maljukova A. Cepeda D. Fiegl H. Dafou D. Marth C. et al.FBXW7/hCDC4 is a general tumor suppressor in human cancer.Cancer Res. 2007; 67: 9006-9012Crossref PubMed Scopus (131) Google Scholarcrosstalk with Wnt and Hippo signalingLung adenocarcinomaoncogenic10% NOTCH1Licciulli et al., 2013Licciulli S. Avila J.L. Hanlon L. Troutman S. Cesaroni M. Kota S. Keith B. Simon M.C. Puré E. Radtke F. et al.Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53.Cancer Res. 2013; 73: 5974-5984Crossref PubMed Scopus (9) Google Scholar, Westhoff et al., 2009Westhoff B. Colaluca I.N. D'Ario G. Donzelli M. Tosoni D. Volorio S. Pelosi G. Spaggiari L. Mazzarol G. Viale G. et al.Alterations of the Notch pathway in lung cancer.Proc. Natl. Acad. Sci. USA. 2009; 106: 22293-22298Crossref PubMed Scopus (115) Google Scholar, Zheng et al., 2013Zheng Y. de la Cruz C.C. Sayles L.C. Alleyne-Chin C. Vaka D. Knaak T.D. Bigos M. Xu Y. Hoang C.D. Shrager J.B. et al.A rare population of CD24(+)ITGB4(+)Notch(hi) cells drives tumor propagation in NSCLC and requires Notch3 for self-renewal.Cancer Cell. 2013; 24: 59-74Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholarrole in initiation and maintenance (Notch1), and metastasis (Jagged2)specific role for Notch3 in tumor propagationGlioblastomaoncogenicrole in tumor propagation and radioresistanceChu et al., 2013Chu Q. Orr B.A. Semenkow S. Bar E.E. Eberhart C.G. ). Prolonged inhibition of glioblastoma xenograft initiation and clonogenic growth following in vivo Notch blockade.Clin. Cancer Res. 2013; 19: 3224-3233Crossref PubMed Scopus (2) Google Scholar, Wang et al., 2010Wang J. Wakeman T.P. Lathia J.D. Hjelmeland A.B. Wang X.F. White R.R. Rich J.N. Sullenger B.A. Notch promotes radioresistance of glioma stem cells.Stem Cells. 2010; 28: 17-28Crossref PubMed Scopus (16) Google ScholarRenal cell carcinomaoncogenicrole in progression and maintenanceSjölund et al., 2008Sjölund J. Johansson M. Manna S. Norin C. Pietras A. Beckman S. Nilsson E. Ljungberg B. Axelson H. Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo.J. Clin. Invest. 2008; 118: 217-228Crossref PubMed Scopus (84) Google ScholarOvarian canceroncogenicrole in maintenance and therapy responseCancer Genome Atlas Research Network., 2011Cancer Genome Atlas Research NetworkIntegrated genomic analyses of ovarian carcinoma.Nature. 2011; 474: 609-615Crossref PubMed Scopus (1152) Google Scholar, McAuliffe et al., 2012McAuliffe S.M. Morgan S.L. Wyant G.A. Tran L.T. Muto K.W. Chen Y.S. Chin K.T. Partridge J.C. Poole B.B. Cheng K.H. et al.Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy.Proc. Natl. Acad. Sci. USA. 2012; 109: E2939-E2948Crossref PubMed Scopus (49) Google ScholarProstateoncogenicactivation of the pathway associated with tumor progression, metastasis, and recurrenceMarignol et al., 2013Marignol L. Rivera-Figueroa K. Lynch T. Hollywood D. Hypoxia, notch signalling, and prostate cancer.Nat. Rev. Urol. 2013; 10: 405-413Crossref PubMed Scopus (10) Google Scholar, Santagata et al., 2004Santagata S. Demichelis F. Riva A. Varambally S. Hofer M.D. Kutok J.L. Kim R. Tang J. Montie J.E. Chinnaiyan A.M. et al.JAGGED1 expression is associated with prostate cancer metastasis and recurrence.Cancer Res. 2004; 64: 6854-6857Crossref PubMed Scopus (168) Google ScholarBreast cancermostly oncogenicNOTCH1 and NOTCH4 fusionsFu et al., 2010Fu Y.P. Edvardsen H. Kaushiva A. Arhancet J.P. Howe T.M. Kohaar I. Porter-Gill P. Shah A. Landmark-Høyvik H. Fosså S.D. et al.NOTCH2 in breast cancer: association of SNP rs11249433 with gene expression in ER-positive breast tumors without TP53 mutations.Mol. Cancer. 2010; 9: 113Crossref PubMed Scopus (23) Google Scholar, Imatani and Callahan, 2000Imatani A. Callahan R. Identification of a novel NOTCH-4/INT-3 RNA species encoding an activated gene product in certain human tumor cell lines.Oncogene. 2000; 19: 223-231Crossref PubMed Google Scholar, Jhappan et al., 1992Jhappan C. Gallahan D. Stahle C. Chu E. Smith G.H. Merlino G. Callahan R. Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands.Genes D
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