p53 homologue, p51/p63, controls keratinocyte proliferation/differentiation due to Notch activity

p53 同源物 p51/p63 通过 Notch 活性控制角质形成细胞增殖/分化

• 批准号: 17591154
• 负责人: OKUYAMA Ryuhei
• 金额: $ 2.24万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591154/
• 关键词: Dermatology; Keratinocytes; p51; Notch; 皮膚

p53 homologue, p51/ p63, predominantly expressed in keratinocyte stem cells, is indispensable for the formation of epidermis. Notch1, another such gene indispensable for the process, induces growth arrest and differentiation in keratinocytes. We found that exogenous expression of ΔNp51B (ΔNp63α), one of the isoforms of p51 specifically expressed in basal keratinocytes, blocked Notch 1 dependent growth arrest and differentiation in mouse keratinocytes by inhibiting p21 expression and maintaining integrins expression. Furthermore, ΔNp51B by itself was found to have ability to induce expression of integrin α6β4, which promotes attachment of basal cells to basal membrane thereby keeping the cells in immature state. Therefore, we conclude that ΔNp51B expression warrants integrin expression even under the influence of Notch1 and that ΔNp51B is a long-sought factor required to maintain basal cell keratinocytes immaturity by inhibiting Notch activity. We will postulate a plausible model explaining the maintenance of the squamous epithelium architectures as well as offering mechanistic explanations for pathological features of skin diseases, including cancers, psoriasis along with physiological wound healings.

P53的同源基因p51/ p63主要在角质细胞干细胞中表达，是表皮形成不可或缺的基因。Notch1是这一过程中不可缺少的另一个基因，它诱导角化细胞的生长停滞和分化。我们发现，在小鼠角质形成细胞中特异性表达的p51亚型之一ΔNp51B （ΔNp63α）的外源表达通过抑制p21的表达和维持整合素的表达，阻断了Notch 1依赖性的生长停滞和分化。此外，ΔNp51B本身能够诱导整合素α6β4的表达，促进基底细胞与基底膜的附着，从而使细胞保持未成熟状态。因此，我们得出结论，即使在Notch1的影响下，ΔNp51B的表达也保证了整合素的表达，并且ΔNp51B是一个长期寻找的因子，通过抑制Notch活性来维持基底细胞角质形成细胞的不成熟。我们将假设一个合理的模型来解释鳞状上皮结构的维持，并为皮肤疾病的病理特征提供机制解释，包括癌症、牛皮癣和生理伤口愈合。

项目成果

Decreased keratinocyte motility in skin wound on mice lacking the epidermal fatty acid binding protein gene

• DOI: 10.1007/s11010-005-9048-8
• 发表时间: 2006-01
• 期刊: Molecular and Cellular Biochemistry
• 影响因子: 4.3
• 作者: Y. Kusakari;E. Ogawa;Y. Owada;Noriko Kitanaka;Hiroshi Watanabe;M. Kimura;H. Tagami;H. Kondo;S. Aiba;R. Okuyama

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

• DOI: 10.1038/sj.onc.1210235
• 发表时间: 2007-07-01
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Okuyama, R.;Ogawa, E.;Ikawa, S.
• 通讯作者: Ikawa, S.

p51/p63, a novel p53 homologue, potentates p53 activity and is a human cancer gene therapy candidate.

p51/p63 是一种新型 p53 同源物，可增强 p53 活性，是人类癌症基因治疗的候选者。

• 发表时间: 2006
• 期刊: j Gene Med 8
• 作者: Kunisaki R;Ikawa S;Maeda T;Nakazaki Y;Kurita R.Harata M;Shutoh Y;Bai YS;Soda Y;Tanabe T;Dobi T;Kato R;Ikawa Y;Asano S;Tani K.
• 通讯作者: Tani K.

Stimulation of Dmc1-mediated DNAA strand exchange by the human Rad54B protein.

人 Rad54B 蛋白刺激 Dmc1 介导的 DNAA 链交换。

• 发表时间: 2006
• 期刊: Nucleic Acid Res 34
• 作者: Shirai S;et al.
• 通讯作者: et al.

Stimulation of Dmc1-mediated DNA strand exchange by the human Rad54B protein

• DOI: 10.1093/nar/gkl562
• 发表时间: 2006-09-01
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Sarai, Naoyuki;Kagawa, Wataru;Yokoyama, Shigeyuki
• 通讯作者: Yokoyama, Shigeyuki