&amp;Delta;Np63&amp;alpha; Levels Correlate with Clinical Tumor Response to Cisplatin

Zangen, Rachel; Ratovitski, Edward A.; Sidransky, David

doi:10.4161/cc.4.10.2066

Cited by 81 publications

(82 citation statements)

References 27 publications

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“…Finally, we showed that the downstream targets affected by the p-DNp63a-dependent modulation of miRNA expression in wild-type DNp63a cells include critical regulators of TP53-dependent and TP53-independent apoptotic genes. 2,[34][35][36] Our data strongly suggest that following CIS exposure, the p-DNp63a transcription factor is likely to play a decisive role in the regulation of certain miRNAs leading to the activation of pro-apoptotic pathways in HNSCC cells. There are two potential mechanisms by which p-DNp63a can regulate miRNA expression: through the DICER1 transcriptional upregulation and subsequent maturation of miRNAs, and/or through direct transcriptional regulation of miRNA gene promoters via formation of protein complexes with other transcriptional and chromatin-associated factors.…”

Section: Discussionmentioning

confidence: 85%

Phospho-ΔNp63α is a key regulator of the cisplatin-induced microRNAome in cancer cells

et al. 2011

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Head and neck squamous cell carcinoma (HNSCC) cells exposed to cisplatin (CIS) displayed a dramatic ATM-dependent phosphorylation of DNp63a that leads to the transcriptional regulation of downstream mRNAs. Here, we report that phospho (p)-DNp63a transcriptionally deregulates miRNA expression after CIS treatment. Several p-DNp63a-dependent microRNA species (miRNAs) were deregulated in HNSCC cells upon CIS exposure, including miR-181a, miR-519a, and miR-374a (downregulated) and miR-630 (upregulated). Deregulation of miRNA expression led to subsequent modulation of mRNA expression of several targets (TP53-S46, HIPK2, ATM, CDKN1A and 1B, CASP3, PARP1 and 2, DDIT1 and 4, BCL2 and BCL2L2, TP73, YES1, and YAP1) that are involved in the apoptotic process. Our data support the notion that miRNAs are critical downstream targets of p-DNp63a and mediate key pathways implicated in the response of cancer cells to chemotherapeutic drugs.

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Section: Discussionmentioning

confidence: 85%

Phospho-ΔNp63α is a key regulator of the cisplatin-induced microRNAome in cancer cells

et al. 2011

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“…Our findings and those of others suggest that ⌬Np63 may also be considered a potential target in a future therapeutic intervention. Interestingly, a recent report 55 documented a correlation between ⌬Np63 overexpression and resistance to cisplatin treatment in certain tumors. Furthermore, ⌬Np63 overexpression conveys resistance to cisplatin and may be used as a surrogate marker for treatment response in certain tumors.…”

Section: Discussionmentioning

confidence: 99%

Expression and Regulation of the ΔN and TAp63 Isoforms in Salivary Gland Tumorigenesis

Mitani

Weber

et al. 2011

The American Journal of Pathology

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The TP63 gene, a TP53 homologue, encodes for two main isoforms by different promoters: one retains (TA) and the other lacks (⌬N) the transactivation domain. p63 plays a critical role in the maintenance of basal and myoepithelial cells in ectodermally derived tissues and is implicated in tumorigenesis of several neoplastic entities. However, the biological and regulatory roles of these isoforms in salivary gland tumorigenesis remain unknown. Our results show a reciprocal expression between TA and ⌬N isoforms in both benign and malignant salivary tumors. The most dominantly expressed were the ⌬N isoforms, whereas the TA isoforms showed generally low levels of expression, except in a few tumors. High ⌬Np63 expression characterized tumors with aggressive behavior, whereas tumors with high TAp63 expression were significantly smaller and less aggressive. In salivary gland cells, high expression of ⌬Np63 led to enhanced cell migration and invasion and suppression of cell senescence independent of TAp63 and/or TP53 gene status. We conclude the following: i) overexpression of ⌬Np63 contributes to salivary tumorigenesis, ii) ⌬Np63 plays a dominant negative effect on the TA isoform in the modulation of cell migration and invasion, and iii) the ⌬N isoform plays an oncogenic role and may represent an attractive target for therapeutic intervention in patients with salivary carcinomas.

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“…Following UVR or treatment with other DNA-damaging agents, ΔNp63 isoforms decrease (28)(29)(30)(31), whereas TAp63 isoforms have been reported to increase following UVR (32,33). ΔNp63α levels have also been reported to predict the clinical response of tumors to cisplatin (34). While p63 has been reported to be important in regulating the apoptotic response following DNA damage (19,28,31,35), its roles in other cellular pathways that respond to genotoxic stress have not yet been defined.…”

Section: Introductionmentioning

confidence: 99%

Impaired repair of cyclobutane pyrimidine dimers in human keratinocytes deficient in p53 and p63

Ferguson-Yates

Dong

et al. 2007

Carcinogenesis

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While many p53-deficient cell types are impaired in global genomic nucleotide excision repair of cyclobutane pyrimidine dimers (CPDs), human epidermal keratinocytes expressing human papillomavirus type 16 E6 and E7 are p53 deficient and yet maintain repair of CPD. We hypothesized that the p53 homolog, p63, may participate in governing global repair instead of p53 in keratinocytes. Following ultraviolet radiation (UVR) of E6/E7 keratinocytes, depletion of p63 but not of p73 impaired global genomic repair of CPD relative to control cells. In all cases, repair of pyrimidine(6-4)pyrimidone photoproducts, the other major UVR-induced DNA lesions, was unaffected. In E6/E7 keratinocytes treated with p63 small interfering RNA, reduced global repair of CPD was associated not with reduced levels of messenger RNA-encoding DNA damage recognition proteins but rather with decreased levels of DDB2 and XPC proteins, suggesting that p63 posttranscriptionally regulates levels of these proteins. These results indicate that global repair may be regulated at multiple levels and suggest a novel role for p63 in modulating repair of DNA damage in human keratinocytes. The results may provide insight into mechanisms of genomic stability in epithelia infected with oncogenic human papilloma viruses and may further explain the lack of increased skin cancer incidence in Li-Fraumeni syndrome.

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ΔNp63α Levels Correlate with Clinical Tumor Response to Cisplatin

Cited by 81 publications

References 27 publications

Phospho-ΔNp63α is a key regulator of the cisplatin-induced microRNAome in cancer cells

Phospho-ΔNp63α is a key regulator of the cisplatin-induced microRNAome in cancer cells

Expression and Regulation of the ΔN and TAp63 Isoforms in Salivary Gland Tumorigenesis

Impaired repair of cyclobutane pyrimidine dimers in human keratinocytes deficient in p53 and p63

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