p51/p63 inhibits ultraviolet B-induced apoptosis via Akt activation

Ogawa, Emiko; Okuyama, Ryuhei; Ikawa, Shuntaro; Nagoshi, Hirokazu; Egawa, Teie; Kurihara, Akira; Yabuki, Masato; Tagami, Hachiro; Obinata, Masuo; Aiba, Setsuya

doi:10.1038/sj.onc.1210682

Cited by 20 publications

(18 citation statements)

References 25 publications

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“…As shown in Figure 7a, UVB irradiation leads to a strong decrease of all FLIP variants; p63 levels are also decreased, in these conditions, as reported earlier. 27,28 As a control for this analysis, we verified the levels of Jun-B, whose expression levels are known to be increased, 29 and (Figure 7a). We overexpressed DNp63a in NHEK, exposed them 24 h after transfection to UVB irradiation, and analysed FLIP by semiquantitative RT-PCR and western blots: we observed increased FLIPr levels, but not of the other two splicing isoforms, FLIPs and FLIPl.…”

Section: Resultsmentioning

confidence: 99%

“…27,28 We investigated whether p63 levels might impact on caspase-8 activation, functionally inactivating p63 in NHEK cells by shRNA: (Figure 3b, and data not shown). Reduction of p63 significantly increased caspase-8 activation, compared with the levels in control cells, as shown in confocal microscopy of irradiated keratinocytes with antibodies against cleaved caspase-8 (Figure 3a and c).…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, in mouse keratinocytes, p63 protects from apoptosis, as assessed by assays of caspase-3 cleavage. 28 Mechanistically, the DNp63a ability to inhibit the proapoptotic function of TAp63 relies on the transcription inhibitory -TI -domain. It was demonstrated that p63 is itself a caspase target: cleavage of TAp63a by activated caspases lead to the loss of the TI domain, enhancing its transcriptional -and proapoptotic -activities.…”

Section: Resultsmentioning

confidence: 99%

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p63 regulates the caspase-8-FLIP apoptotic pathway in epidermis

et al. 2008

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The transcription factor p63, member of the p53 family, is crucial for epithelial development. An RNAi screening identified the apoptotic gene Procaspase-8 as a target activated by p63. The caspase-8 inhibitor FLIP is also under p63 control. We analysed and detailed the direct transactivation through the use of RNAi, reporter assays, ChIPs, western blots, confocal studies in HaCat, as well as in primary human keratinocytes. The direct DNp63 regulation of these targets was confirmed in vivo using transgenic DNp63 mice under the K5 promoter, as compared with p63 knockout mice, and in vitro in normal human primary keratinocytes following UV irradiation. Lowering the steady state of p63 protein levels changes the relative ratio of FLIP isoforms, causing the activation of the expressed, inactive Procaspase-8, into the active isoform thus triggering the proapoptotic cascade. Therefore, p63 fine-tunes the Procaspase-8-FLIP pro-and antiapoptotic pathway in keratinocytes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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p63 regulates the caspase-8-FLIP apoptotic pathway in epidermis

et al. 2008

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“…During the past few years it has been suggested that DNp63 acts as an antiapoptotic factor in both cancer and development (Carroll et al, 2006;Cheng et al, 2006;Lee et al, 2006;Ogawa et al, 2008;Borrelli et al, 2009;Mundt et al, 2010). During mammalian development, apoptosis in the bladder epithelium is increased in the absence of DNp63; however, the restitution of DNp63 expression reverses the increased levels of apoptosis in the urothelium .…”

Section: Dnp63 Is An Anti-apoptotic Factor During Epidermal Developmentmentioning

confidence: 94%

ΔNp63 is regulated by BMP4 signaling and is required for early epidermal development in Xenopus

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et al. 2011

Developmental Dynamics

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Background: It has been established in several models that the p63 gene has an important role in the development of the epidermis and its derivatives. In Xenopus, only the DNp63 isoform of this gene has been cloned and its role during epidermal development remains unknown. Results: In this work, we showed that DNp63 is expressed in the nonneural ectoderm since the gastrula stage and that it is regulated by the bone morphogenetic protein 4 (BMP4) signaling pathway. Our in vivo and in vitro experiments demonstrated that DNp63 is required in the earliest inductive steps of epidermal development. The overexpression of DNp63 caused an increase in epidermal markers with a suppression of neural induction while the blocking of DNp63 led to the opposite results. Finally, we found that DNp63 acts as an anti-apoptotic gene, regulating the transcription of some apoptotic and anti-apoptotic factors. Conclusion: The results suggest that DNp63 is an essential gene in early epidermal specification under the control of BMP4. Developmental Dynamics 241:257-269,

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“…7,8 The survival factor Akt can increase DNp63a levels and in turn, DNp63a protects against UV-B-induced apoptosis via Akt activation. 9,10 However, the mechanism behind the positive feedback loop between DNp63a and Akt has not been described. Akt activation can be negated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN).…”

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ΔNp63α regulates keratinocyte proliferation by controlling PTEN expression and localization

et al. 2011

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DNp63a, implicated as an oncogene, is upregulated by activated Akt, part of a well-known cell survival pathway. Inhibition of Akt activation by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and the presence of putative p63-binding sites in the pten promoter led us to investigate whether DNp63a regulates PTEN expression. Knockdown of DNp63a led to increases in PTEN levels and loss of activated Akt, while overexpression of DNp63a decreased PTEN levels and elevated active Akt. The repression of PTEN by DNp63a occurs independently of p53 status, as loss of DNp63a increases PTEN expression in cell lines with and without functional p53. In addition, decreased levels of DNp63a resulted in an increase in nuclear PTEN. Conversely, in vivo nuclear PTEN was absent in the proliferative basal layer of the epidermis where DNp63a expression is highest. Additionally, we show that in keratinocytes a balance between DNp63a and PTEN regulates Akt activation and maintains normal proliferation rates. This balance is disrupted in non-melanoma skin cancers through increased DNp63a levels, and could enhance proliferation and subsequent neoplastic development. Our studies show that DNp63a negatively regulates PTEN, thereby providing a feedback loop between PTEN, Akt and DNp63a, which has an integral role in skin cancer development. Cell Death and Differentiation (2011) 18, 1924-1933 doi:10.1038/cdd.2011; published online 3 June 2011The p53 transcription factor family consists of the tumor suppressor p53 and the homologous p63 and p73. Unlike p53, p63 is essential for normal epidermal stratification and the proliferative potential of the epithelial stem cells. 1,2 p63 exists as various isoforms with contrasting functions. 2 The TA isoforms (TAp63a, TAp63b and TAp63g) have a full-length N-terminal transactivation domain, whereas the DN isoforms (DNp63a, DNp63b and DNp63g) have a short but distinct transactivation domain. All isoforms have a DNA-binding domain that shares high homology with p53 that allows p63 proteins to bind to p53 DNA-binding sites. 3,4 Similar to p53, the TA isoforms of p63 and p73 can promote apoptosis and growth arrest through the induction of antiproliferative genes. In contrast, the DN isoforms have been shown to induce pro-survival genes and inhibit anti-proliferative genes. [4][5][6] Several studies indicate that DNp63a, the predominant isoform in adult tissue, may function as an oncogene as it can exert a dominant-negative effect over p53 and the TAp63 and TAp73 isoforms. 2 Additionally, DNp63a is frequently overexpressed in a variety of squamous cell (SCC) and basal cell carcinomas (BCCs). 7,8 The survival factor Akt can increase DNp63a levels and in turn, DNp63a protects against UV-B-induced apoptosis via Akt activation. 9,10 However, the mechanism behind the positive feedback loop between DNp63a and Akt has not been described. Akt activation can be negated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN). PTEN dephosphorylates phosphatidylinositol 3,4,5-trisphosphate, thereby...

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p51/p63 inhibits ultraviolet B-induced apoptosis via Akt activation

Cited by 20 publications

References 25 publications

p63 regulates the caspase-8-FLIP apoptotic pathway in epidermis

p63 regulates the caspase-8-FLIP apoptotic pathway in epidermis

ΔNp63 is regulated by BMP4 signaling and is required for early epidermal development in Xenopus

ΔNp63α regulates keratinocyte proliferation by controlling PTEN expression and localization

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