p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity

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

doi:10.1038/sj.onc.1210235

Cited by 65 publications

(68 citation statements)

References 39 publications

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“…The cell cycle was not significantly perturbed by the overexpression of DNp51B or TAp51B, as judged by flow cytometry (Figure 3f). This was consistent with our previous observation that p51 overexpression by itself does not affect keratinocyte proliferation (Okuyama et al, 2007). These results indicate that inhibition of UV-B-induced apoptosis by p51 is not dependent on its ability to induce cell cycle arrest.…”

Section: P51 Blocks Apoptosis Of Uv-b-irradiated Keratinocytessupporting

confidence: 93%

“…However, in this study, the DN and TAp51 isoforms acted similarly to alleviate the UV-B-induced apoptosis. We also found that both isoforms act similarly in inhibiting keratinocyte growth arrest and differentiation, which is critical for maintaining keratinocyte stem cells and the architecture of the squamous epithelium (Okuyama et al, 2007). The similar effects of the DNp51 and TA isoforms may have been mediated by an ancillary transactivation domain within the NH 2 terminus of the DN variant (Dohn et al, 2001).…”

Section: P51-dependent Protection Of Uv-b-irradiated Keratinocytes Ismentioning

confidence: 58%

“…To examine the roles of p51 after birth, we used a primary mouse keratinocyte culture system to elucidate the function of p51 in UV-Birradiated keratinocytes. We found that one of the functions of the DNp51B isoform after birth is to maintain the epidermal stem cell population and stratified epithelia (Okuyama et al, 2007). In the present study, we describe for the first time that p51 blocks apoptosis by activating Akt (also known as protein kinase B), a cytoplasmic serine/threonine kinase, which triggers the cell survival pathway.…”

Section: Introductionmentioning

confidence: 53%

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

et al. 2007

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The epidermis must be protected against excess apoptotic cell death in response to ultraviolet-B (UV-B) irradiation. p53 is known to be critical for this protection. Although the p53 family member DNp51B/DNp63a (an N terminaldeleted form of p51/p63) is abundantly expressed in keratinocytes, its contribution to UV-B-dependent apoptosis is largely unknown. We found that, after a transient increase, DNp51B is downregulated in UV-B-irradiated keratinocytes undergoing apoptosis, whereas p53 is upregulated with delayed kinetics. Furthermore, the reduction of DNp51B by small interfering RNAs augmented UV-B-dependent apoptosis in keratinocytes, indicating that DNp51B blocks keratinocyte apoptosis. Although the exogenous expression of DNp51B in keratinocytes did not further block the UV-B-dependent apoptosis, to our surprise the expression of TAp51B (an isoform with a full NH 2 -terminal transactivation domain that is structurally and functionally similar to p53) decreased apoptosis significantly. The blockade of keratinocyte apoptosis by the p51 was dependent on the phosphorylation of Akt, resulting in the activation of a survival pathway. Thus, in addition to its indispensable roles in epithelial development, p51 acts in adult cells to protect the epidermis against UV-B irradiation by preventing excess depletion of keratinocytes.

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Section: P51 Blocks Apoptosis Of Uv-b-irradiated Keratinocytessupporting

confidence: 93%

Section: P51-dependent Protection Of Uv-b-irradiated Keratinocytes Ismentioning

confidence: 58%

Section: Introductionmentioning

confidence: 53%

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

et al. 2007

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“…Consistently, p53 down regulation rescues the cell proliferation defect due to a p63 knockdown, but not the incapacity of p63-less cells to differentiate [29,30]. An additional signaling pathway playing a crucial role in epidermal stratification and keratinocytes differentiation is through Notch [39][40][41][42][43]. Although several evidences indicate that p63 functions as a modulator of Notch1-dependent transcription and function and also directly transactivates the Notch ligand, JAGG-1 [39], the role of p63 in modulating Notch signaling is not clear.…”

Section: Transcriptional Activities Of P63 Isoformsmentioning

confidence: 65%

p63 in epithelial development

Candi

Cipollone

Cervo

et al. 2008

Cell. Mol. Life Sci.

120

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List of abbreviations: K, keratin; p63-/-, mouse knockout for p63; p63-/-;TA, p63 knockout mice complemented with TAp63; p63-/-;ΔN, p63 knockout mice complemented with ΔNp63; p63-/-;TA;ΔN, p63 knockout mice complemented with both TAp63 and ΔNp63;IKKα, IkB kinase-α; TA, transactivation domain; ΔN, amino-terminal truncated protein. AbstractThe epidermis, the outer layer of the skin composed of keratinocytes, is a stratified epithelium that functions as a barrier to protect the organism from dehydration and external insults. The epidermis develops following the action of the transcription factor p63, a member of the p53 family of transcription factors. The Trp63 gene contains two promoters, driving the production of distinct proteins, one with an N-terminal transactivation domain (TAp63) and one without (DeltaNp63), although their relative contribution to epidermal development is not clearly established. Trp63 mutations are involved in the pathogenesis of several human diseases, phenotypically characterized by ectodermal dysplasia. In this review we summarise the current advances that have been made in understanding the role of p63 in epidermal morphogenesis.

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“…Mechanistic studies suggest the overexpression of ΔNp63 enhanced by PI3K on 3q may also suppress NOTCH expression and tumor suppressor function 22, 23. Tumors with loss of NOTCH1 are more poorly differentiated and have been associated with worse prognosis 24.…”

Section: Resultsmentioning

confidence: 99%

Genomics and advances towards precision medicine for head and neck squamous cell carcinoma

Waes

Musbahi

2017

Laryngoscope Investig Oto

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ObjectiveTo provide a review of emerging knowledge from genomics and related basic science, preclinical, and clinical precision medicine studies in head and neck squamous cell carcinoma (HNSCC).Data SourcesThe Cancer Genome Atlas Network (TCGA) publications, PubMed‐based literature review, and ClinicalTrials.gov.Review MethodsTCGA publications, PubMed, and ClinicalTrials.gov were queried for genomics and related basic science, preclinical, and developmental clinical precision medicine studies in HNSCC.ResultsTCGA reported comprehensive genomic analyses of 279 HNSCC, defining the landscape and frequency of chromosomal copy number alterations, mutations, and expressed genes that contribute to pathogenesis, prognosis, and resistance to therapy. This provides a road map for basic science and preclinical studies to identify key pathways in cancer and cells of the tumor microenvironment affected by these alterations, and candidate targets for new small molecule and biologic therapies.ConclusionRecurrent chromosomal abnormalities, mutations, and expression of genes affecting HNSCC subsets are associated with differences in prognosis, and define molecules, pathways, and deregulated immune responses as candidates for therapy. Activity of molecularly targeted agents appears to be enhanced by rational combinations of these agents and standard therapies targeting the complex alterations that affect multiple pathways and mechanisms in HNSCC.Level of EvidenceNA.

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p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity

Cited by 65 publications

References 39 publications

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

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

p63 in epithelial development

Genomics and advances towards precision medicine for head and neck squamous cell carcinoma

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