RACK1 and Stratifin Target &amp;Delta;Np63&amp;alpha; for a Proteasome Degradation in Head and Neck Squamous Cell Carcinoma Cells upon DNA Damage

Fomenkov, Alexey; Zangen, Rachel; Huang, Yi Ping; Osada, Motonobu; Guo, Zhen; Fomenkov, Tanya; Trink, Barry; Sidransky, David; Ratovitski, Edward A.

doi:10.4161/cc.3.10.1155

Cited by 95 publications

(125 citation statements)

References 52 publications

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“…In addition, p63 has been reported to be important for the apoptotic response independent of p53 (35), and the ΔNp63 isoform in particular has been shown to be critical for preventing apoptosis in keratinocytes following UVR as well as in other cell types following DNA damage (19,28,31,35). However, a role for p63 in tumorigenesis is still unclear.…”

Section: Discussionmentioning

confidence: 95%

“…p63 clearly plays a critical role in epidermal development and homeostasis both in mice and humans (15)(16)(17), but it is still unclear if p63 plays a role in carcinogenesis. While p63 has been reported to be absent or reduced in some human cancers, including basal cell carcinomas (18), it has more frequently been reported to be overexpressed in various tumors (19,20), including non-melanoma skin cancers (21)(22)(23)(24). Similarly, conflicting data from mice heterozygous for p63 have not resolved whether p63 is a tumor suppressor or oncogene (25)(26)(27).…”

Section: Introductionmentioning

confidence: 88%

“…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. We hypothesized that p63 may be a tissue-specific candidate for maintaining GGR selectively in keratinocytes, even in the absence of p53.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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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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“…Increasing evidence suggests that protein ubiquitination and degradation have an important function for the p63 activity. [23][24][25]33 Two other WWP1 family members, Itch and Nedd4, have been previously reported to target p63 proteins for proteasomal degradation. 24,25 However, the expression levels of Itch in breast cancer are not altered 34 although the expression of Nedd4 has been found to be overexpressed in invasive bladder cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…22 The receptor of activated protein C kinase-Elongin-C/B ubiquitin ligase complex has been proposed to be an E3 ligase for DNp63a. 23 Recently, two WWP1 family members, Itch and Nedd4 have been shown to promote ubiquitination and degradation of the p63 proteins. 24,25 In addition, the inhibition of Itch potentiates the killing effect of doxorubicin in HeLa cells.…”

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confidence: 99%

WW domain-containing E3 ubiquitin protein ligase 1 targets p63 transcription factor for ubiquitin-mediated proteasomal degradation and regulates apoptosis

2008

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WWP1 E3 ubiquitin ligase has previously been shown to be frequently amplified and overexpressed in prostate and breast cancers. However, the mechanism of WWP1 action is still largely unknown. p63, a member of the p53 family of transcription factors, has an important function in tumor development by regulating apoptosis. Using alternative promoters, p63 can be expressed as DNp63 and TAp63. Increasing evidence suggests that TAp63 sensitizes cells to apoptosis but DNp63 has an opposite function. In this study, we show that WWP1 binds, ubiquitinates, and destructs both DNp63a and TAp63a. The proteinprotein interaction occurs between the PY motif of p63 and the WW domains of WWP1. The knockdown of WWP1 by siRNA increases the endogenous DNp63a level in the MCF10A and 184B5 immortalized breast epithelial cell lines and confers resistance to doxorubicin-induced apoptosis. On the other hand, the knockdown of WWP1 increases the endogenous level of TAp63a, induces apoptosis, and increases sensitivity to doxorubicin and cisplatin in the HCT116 colon cancer cell line in a p53-independent manner. Finally, we found that DNA damage chemotherapeutic drugs induce WWP1 mRNA and protein expression in a p53-dependent manner. These data suggest that WWP1 may have a context-dependent role in regulating cell survival through targeting different p63 proteins for degradation.

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ΔNp63 in squamous cell carcinoma: defining the oncogenic routes affecting epigenetic landscape and tumour microenvironment

Gatti

Fernanda

Annicchiarico-Petruzzelli

et al. 2019

Molecular Oncology

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Squamous cell carcinoma ( SCC ) is a treatment‐refractory tumour which arises from the epithelium of diverse anatomical sites such as oesophagus, head and neck, lung and skin. Accumulating evidence has revealed a number of genomic, clinical and molecular features commonly observed in SCC of distinct origins. Some of these genetic events culminate in fostering the activity of ΔNp63, a potent oncogene which exerts its pro‐tumourigenic effects by regulating specific transcriptional programmes to sustain malignant cell proliferation and survival. In this review, we will describe the genetic and epigenetic determinants underlying ΔNp63 oncogenic activities in SCC , and discuss some relevant transcriptional effectors of ΔNp63, emphasizing their impact in modulating the crosstalk between tumour cells and tumour microenvironment ( TME ).

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RACK1 and Stratifin Target ΔNp63α for a Proteasome Degradation in Head and Neck Squamous Cell Carcinoma Cells upon DNA Damage

Cited by 95 publications

References 52 publications

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

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

WW domain-containing E3 ubiquitin protein ligase 1 targets p63 transcription factor for ubiquitin-mediated proteasomal degradation and regulates apoptosis

ΔNp63 in squamous cell carcinoma: defining the oncogenic routes affecting epigenetic landscape and tumour microenvironment

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