p53 Family: Role of Protein Isoforms in Human Cancer

Wei, Jinxiong; Zaika, Elena; Zaika, Alexander

doi:10.1155/2012/687359

Cited by 86 publications

(86 citation statements)

References 153 publications

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“…P2 alternative promoters produce transactivation domain-deficient proteins (ΔN) with dominant-negative functions. Heterocomplexes with ΔN forms compete off long-TA (entire transactivation domain) isoforms from their target gene promoters, thereby preventing efficient transcription (47). Our data reveal a number of HDM201-resistant tumors with unidirectional insertions in Trp63 and Trp73 and consistent protein overexpression (Fig.…”

Section: Identification Of Mechanisms Of Resistance To Tp53-mdm2 Inhimentioning

confidence: 78%

“…4 G-J). Transposon insertions were located specifically near P2 promoters, suggesting the expression of truncated variants similar to ΔNTrp73 and ΔNTrp63, consistent with a dominant negative function on TRP53 (47).…”

Section: Identification Of Mechanisms Of Resistance To Tp53-mdm2 Inhimentioning

confidence: 84%

“…Thus, specific MDM4 antagonists may provide therapeutic benefits in cases where resistance occurs by MDM4 overexpression in wild-type TP53 tumors. ΔN isoforms of Trp73 and Trp63 are produced by an alternative promoter and lack the transactivation domain (47). They are suspected to exhibit proto-oncogenic function and TP53 dominant-negative functions.…”

Section: Discussionmentioning

confidence: 99%

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Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Chapeau

Gembarska

Durand

et al. 2017

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

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Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which the TP53 gene is wild type, by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201. Constitutive PB mutagenesis in Arf −/− mice provided a collection of spontaneous tumors with characterized insertional genetic landscapes. Tumors were allografted in large cohorts of mice to assess the pharmacologic effects of HDM201. Sixteen out of 21 allograft models were sensitive to HDM201 but ultimately relapsed under treatment. A comparison of tumors with acquired resistance to HDM201 and untreated tumors identified 87 genes that were differentially and significantly targeted by the PB transposon. Resistant tumors displayed a complex clonality pattern suggesting the emergence of several resistant subclones. Among the most frequent alterations conferring resistance, we observed somatic and insertional loss-of-function mutations in transformation-related protein 53 (Trp53) in 54% of tumors and transposonmediated gain-of-function alterations in B-cell lymphoma-extra large (Bcl-xL), Mdm4, and two TP53 family members, resulting in expression of the TP53 dominant negative truncations ΔNTrp63 and ΔNTrp73. Enhanced BCL-xL and MDM4 protein expression was confirmed in resistant tumors, as well as in HDM201-resistant patient-derived tumor xenografts. Interestingly, concomitant inhibition of MDM2 and BCL-xL demonstrated significant synergy in p53 wild-type cell lines in vitro. Collectively, our findings identify several potential mechanisms by which TP53 wild-type tumors may escape MDM2-targeted therapy.drug resistance | MDM2 inhibitor | piggyBac screen | cancer A mong the genes most commonly altered in human cancer, regardless of tumor type, are tumor protein 53 (TP53) tumor suppressor (1) and CDKN2A (INK4a/ARF) (2). The latter gene encodes two tumor suppressor proteins: p16INK4a (3), an inhibitor of cyclin D-dependent kinases that, at least in part, regulates the function of the retinoblastoma protein (RB), and p19ARF (4), a negative regulator of double minute 2 protein (MDM2) function that activates TP53, thereby inducing cell cycle arrest or apoptosis. TP53 protein levels are regulated through MDM2-mediated degradation.Toward the goal of reactivating TP53 in cells harboring inactivating upstream pathway alterations, compounds inhibiting the interaction between MDM2 and TP53, preventing TP53 degradation, have been discovered. Such agents induce TP53 reactivation in tumors in which the TP53 gene is wild type (5-8).Although preclinical studies of such MDM2 inhibitors have demonstrated significant antitumor activity, tumors commonly relapse (9, 10).Rapid emergence of resistance is...

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Section: Identification Of Mechanisms Of Resistance To Tp53-mdm2 Inhimentioning

confidence: 78%

Section: Identification Of Mechanisms Of Resistance To Tp53-mdm2 Inhimentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Chapeau

Gembarska

Durand

et al. 2017

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

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“…P73 was identified to be a member of the p53 family and is frequently overexpressed in human tumors (12)(13)(14). Although p53 is firmly established to be a tumor suppressor, the role of p73 in human tumorigenesis is not well understood (15,16).…”

Section: Introductionmentioning

confidence: 99%

Zoledronic acid inhibits the pentose phosphate pathway through attenuating the Ras-TAp73-G6PD axis in bladder cancer cells

Wang

Cao

et al. 2015

Molecular Medicine Reports

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Abstract. Zoledronic acid (ZA) is the current standard of care for the therapy of patients with bone metastasis or osteoporosis. ZA inhibits the prenylation of small guanosine-5'-triphosphate (GTP)-binding proteins, such as Ras, and thus inhibit Ras signaling. The present study demonstrated that ZA inhibited cell proliferation and the pentose phosphate pathway (PPP) in bladder cancer cells. In addition, the expression of glucose-6-phosphate dehydrogenase (G6PD, the rate-limiting enzyme of the PPP) was found to be inhibited by ZA. Furthermore, the stability of TAp73, which activates the expression G6PD was decreased in zoledronic acid treated cells. Decreased levels of Ras-GTP and phosphorylated-extracellular signal-regulated kinase 1/2 were also observed following treatment with ZA. This may be due to the fact that activated Ras was reported to stabilize TAp73 inducing its accumulation. The inhibition of Ras activity by PT inhibitor II also significantly reduced the levels of TAp73 and G6PD and the PPP flux. Moreover, knockdown of TAp73, attenuated the PPP flux and eliminated the affection of ZA on the PPP flux. In conclusion, it was proposed that ZA can inhibit stability of TAp73 and attenuate the PPP via blocking Ras signaling in bladder cancer cells.

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“…In human colon adenomas, the Δ133p53 isoform has been found to inhibit p53-mediated replicative senescence, and its increase may signal an escape from the senescence barrier during the progression from adenoma to carcinoma (10). Elevated levels of Δ133p53 have also been reported in a number of human tumors (11).…”

mentioning

confidence: 99%

Pathogenic bacterium Helicobacter pylori alters the expression profile of p53 protein isoforms and p53 response to cellular stresses

Wei

Noto

Zaika³

et al. 2012

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

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The p53 protein plays a central role in the prevention of tumorigenesis. Cellular stresses, such as DNA damage and aberrant oncogene activation, trigger induction of p53 that halts cellular proliferation and allows cells to be repaired. If cellular damage is beyond the capability of the repair mechanisms, p53 induces apoptosis or cell cycle arrest, preventing damaged cells from becoming cancerous. However, emerging evidence suggests that the function of p53 needs to be considered as isoform-specific. Here, we report that the expression profile of p53 can be shifted toward inhibitory p53 isoforms by the pathogenic bacterium Helicobacter pylori, which is known for its strong association with gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. We found that interaction of H. pylori with gastric epithelial cells, mediated via the cag pathogenicity island, induces N-terminally truncated ∆133p53 and ∆160p53 isoforms in human cells. Induction of an orthologous p53 isoform, ∆153p53, was also found in H. pylori-infected Mongolian gerbils. The p53 isoforms inhibit p53 and p73 activities, induce NF-κB, and increase survival of infected cells. Expression of ∆133p53, in response to H. pylori infection, is regulated by phosphorylation of c-Jun and activation of activator protein-1–dependent transcription. Together, these results provide unique insights into the regulation of p53 protein and may contribute to the understanding of tumorigenesis associated with H. pylori.

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p53 Family: Role of Protein Isoforms in Human Cancer

Cited by 86 publications

References 153 publications

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Zoledronic acid inhibits the pentose phosphate pathway through attenuating the Ras-TAp73-G6PD axis in bladder cancer cells

Pathogenic bacterium Helicobacter pylori alters the expression profile of p53 protein isoforms and p53 response to cellular stresses

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p53 Family: Role of Protein Isoforms in Human Cancer

Cited by 86 publications

References 153 publications

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf −/− mouse model

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf −/− mouse model

Zoledronic acid inhibits the pentose phosphate pathway through attenuating the Ras-TAp73-G6PD axis in bladder cancer cells

Pathogenic bacterium Helicobacter pylori alters the expression profile of p53 protein isoforms and p53 response to cellular stresses

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Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf ^−/− mouse model