Analysis of genetic and epigenetic processes that influence p14ARF expression in breast cancer

Silva, Javier; Domínguez, Gemma; Silva, José M.; García, José M.; Gallego, Isabel; Corbacho, C.; Provencio, Mariano; España, Pilar; Bonilla, Félix

doi:10.1038/sj.onc.1204617

Cited by 48 publications

(33 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the case of breast cancer, inactivating mutations of the TP53 gene, or alterations of circuitries regulating TP53 levels are relatively infrequent (21)(22)(23)(24)(25)(26)(27)(28), thereby providing a strong rationale for how loss of NUMB and the ensuing increased TP53 degradation can confer a proliferative advantage (17). The situation is different in NSCLCs, which are characterized by a high frequency of mutations of the TP53 gene (29).…”

Section: Discussionmentioning

confidence: 99%

Alterations of the Notch pathway in lung cancer

Westhoff

Colaluca

Giorgini

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

349

299

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Alterations of the Notch pathway in lung cancer

Westhoff

Colaluca

Giorgini

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

349

299

View full text Add to dashboard Cite

“…INK4a (12), p15 INK4b (13), and p14 ARF (14); apoptosis-related genes such as DAPK (15); and genes involved in the removal and attenuation of oxidative-free radicals, MnSOD (16) and GSTP-1 (17), are all inactivated by promoter methylation. A likely cause of this inactivation is the binding of 5-methylcytosine specific proteins to CpG sites, which interferes with the binding of transcription factors necessary for gene expression (18).…”

Section: Introductionmentioning

confidence: 99%

Interleukin 6 Supports the Maintenance of p53 Tumor Suppressor Gene Promoter Methylation

Hodge

Peng

Cherry³

et al. 2005

Cancer Research

205

133

View full text Add to dashboard Cite

A strong association exists between states of chronic inflammation and cancer, and it is believed that mediators of inflammation may be responsible for this phenomenon. Interleukin 6 (IL-6) is an inflammatory cytokine known to play a role in the growth and survival of many types of tumors, yet the mechanisms employed by this pleomorphic cytokine to accomplish this feat are still poorly understood. Another important factor in tumor development seems to be the hypermethylation of CpG islands located within the promoter regions of tumor suppressor genes. This common epigenetic alteration enables tumor cells to reduce or inactivate the expression of important tumor suppressor and cell cycle regulatory genes. Here we show that in the IL-6-responsive human multiple myeloma cell line KAS 6/1, the promoter region of p53 is epigenetically modified by methyltransferases, resulting in decreased levels of expression. Furthermore, cells treated with IL-6 exhibit an increase in the expression of the DNA maintenance methylation enzyme, DNMT-1. The DNA methyltransferase inhibitor zebularine reverses the methylation of the p53 promoter, allowing the resumption of its expression. However, when zebularine is withdrawn from the cells, the reestablishment of the original CpG island methylation within the p53 promoter does not occur in the absence of IL-6, and cells which do not receive IL-6 eventually die, as p53 expression continues unchecked by remethylation. Interestingly, this loss of viability seems to involve not the withdrawal of cytokine, but the inability of the cell to resilence the promoter. Consistent with this model, when cells that express IL-6 in an autocrine fashion are subjected to identical treatment, p53 expression is reduced shortly after withdrawal of zebularine. Therefore, it seems IL-6 is capable of maintaining promoter methylation thus representing one of the possible mechanisms used by inflammatory mediators in the growth and survival of tumors. (Cancer Res 2005; 65(11): 4673-82)

show abstract

“…Thus, overexpression or amplification of mouse double minute (mdm2), the gene encoding the E3-ubiquitin ligase that targets p53 for degradation by the proteasome, is frequent in prostate cancer, whereas overexpression of the p53 transcriptional inhibitor MdmX is common in retinoblastoma (6,7). In some breast, brain, and lung tumors, the upstream inhibitor of Mdm2 activity, p14 ARF , is inactivated by gene loss, methylation, or repression (8)(9)(10)(11)(12), thus uncoupling p53 activation from oncogenic signaling (13,14). Finally, in tumors associated with DNA tumor viruses such as HPV, simian vacuolating virus 40, and adenovirus, p53 typically is inactivated directly by viral oncoproteins.…”

mentioning

confidence: 99%

Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy

Shchors

Persson

Rostker

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Based on clinical presentation, glioblastoma (GBM) is stratified into primary and secondary types. The protein 53 (p53) pathway is functionally incapacitated in most GBMs by distinctive type-specific mechanisms. To model human gliomagenesis, we used a GFAPHRas V12 mouse model crossed into the p53ER TAM background, such that either one or both copies of endogenous p53 is replaced by a conditional p53ER TAM allele. The p53ER TAM protein can be toggled reversibly in vivo between wild-type and inactive conformations by administration or withdrawal of 4-hydroxytamoxifen (4-OHT), respectively. Surprisingly, gliomas that develop in GFAP-HRas V12 ; p53 +/KI mice abrogate the p53 pathway by mutating p19 ARF / MDM2 while retaining wild-type p53 allele. Consequently, such tumors are unaffected by restoration of their p53ER TAM allele. By contrast, gliomas arising in GFAP-HRas V12 ;p53 KI/KI mice develop in the absence of functional p53. Such tumors retain a functional p19 ARF /MDM2-signaling pathway, and restoration of p53ER TAM allele triggers p53-tumor-suppressor activity. Congruently, growth inhibition upon normalization of mutant p53 by a small molecule, Prima-1, in human GBM cultures also requires p14 ARF /MDM2 functionality. Notably, the antitumoral efficacy of p53 restoration in tumor-bearing GFAP-HRas V12 ;p53 KI/KI animals depends on the duration and frequency of p53 restoration. Thus, intermittent exposure to p53ER TAM activity mitigated the selective pressure to inactivate the p19 ARF /MDM2/p53 pathway as a means of resistance, extending progression-free survival. Our results suggest that intermittent dosing regimes of drugs that restore wild-type tumorsuppressor function onto mutant, inactive p53 proteins will prove to be more efficacious than traditional chronic dosing by similarly reducing adaptive resistance.preclinical model | Nutlin 3 | intermittent treatment

show abstract

Analysis of genetic and epigenetic processes that influence p14ARF expression in breast cancer

Cited by 48 publications

References 21 publications

Alterations of the Notch pathway in lung cancer

Alterations of the Notch pathway in lung cancer

Interleukin 6 Supports the Maintenance of p53 Tumor Suppressor Gene Promoter Methylation

Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy

Contact Info

Product

Resources

About