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首页> 外文学位 >Role of p38delta and MEP50 in Epidermal Keratinocyte Homeostasis.
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Role of p38delta and MEP50 in Epidermal Keratinocyte Homeostasis.

机译：p38delta和MEP50在表皮角质形成细胞稳态中的作用。

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摘要

Keratinocytes are the major cell type in the human epidermis, the outer layer of skin. These cells undergo a tightly regulated terminal differentiation program which results in the formation of the cornified envelope. This envelope is essentially the barrier which protects us from mechanical stress, extreme climate conditions and infectious agents. A fully functional epidermal barrier dictates a perfect balance between proliferation and differentiation. PKCdelta, a novel PKC isoform and a key controller of epidermal differentiation regulates proliferation by increasing p21Cip1 expression. However, little is known about the mediators involved in this regulation. We hypothesize that p38delta MAPK, a downstream kinase is a mediator in this process. We observe that p38delta regulates p21Cip1 mRNA/protein levels in a p53 dependent manner. Additionally, PKCdelta selectively activates p38delta and treatment with p38delta-siRNA or dominant negative p38 results in attenuation of the PKCdelta induced p21Cip1 response. Furthermore, p53 is identified as a novel target of p38delta and is a key mediator in the p38delta-p21Cip1 signaling cascade. Moreover, the physiological relevance of this pathway is confirmed in the PKCdelta and p38delta knockdown organotypic cultures which are thicker, have additional layers and reduced cornified envelope formation as compared to the controls. We have also identified the Protein Arginine Methyltransferase (PRMT5) and Methylosome Protein 50 (MEP50) as novel targets of PKCdelta and p38delta and MEP50 enhances keratinocyte proliferation and opposes differentiation by mechanisms involving silencing p21Cip1 and involucrin. We found that symmetric demethylation of arginines in histones H3 and H4 plays a key role in this regulation. Additionally, the pro-proliferation role of MEP50 is physiologically relevant as MEP50 knockdown rafts are significantly thinner and have fewer number of Ki67 positive cells than the control rafts. These studies highlight p38delta as a common kinase regulating the dual processes of proliferation and differentiation and characterize the role of MEP50/PRMT5 as novel players in controlling epidermal homeostasis.
机译：角质形成细胞是人表皮（皮肤外层）中的主要细胞类型。这些细胞经过严格调节的终末分化程序，导致形成角质化包膜。这个信封实际上是保护我们免受机械压力，极端气候条件和传染原的屏障。功能齐全的表皮屏障决定了增殖与分化之间的完美平衡。 PKCdelta，一种新型的PKC亚型，是表皮分化的关键控制因子，可通过增加p21Cip1表达来调节增殖。但是，对于涉及该法规的调解员知之甚少。我们假设下游过程中的激酶p38delta MAPK是该过程的介体。我们观察到p38delta以p53依赖性方式调节p21Cip1 mRNA /蛋白质水平。此外，PKCdelta选择性激活p38delta，用p38delta-siRNA或显性阴性p38处理会导致PKCdelta诱导的p21Cip1反应减弱。此外，p53被鉴定为p38delta的新型靶标，并且是p38delta-p21Cip1信号级联反应中的关键介体。而且，在PKCdelta和p38delta敲除的器官型培养物中证实了该途径的生理相关性，与对照相比，PKCdelta和p38delta敲除的器官型培养物更厚，具有附加的层并减少了角质化的包膜形成。我们还确定了蛋白质精氨酸甲基转移酶（PRMT5）和甲基脂质体蛋白50（MEP50）作为PKCdelta和p38delta的新靶标，并且MEP50通过涉及p21Cip1和involucrin沉默的机制增强了角质形成细胞增殖并反对分化。我们发现组蛋白H3和H4中精氨酸的对称去甲基化在该调控中起关键作用。另外，MEP50的增殖作用在生理上是相关的，因为MEP50敲除筏比对照筏明显更薄并且Ki67阳性细胞数量更少。这些研究突显了p38δ是调节增殖和分化双重过程的常见激酶，并表征了MEP50 / PRMT5作为控制表皮稳态的新角色。

著录项

  • 作者

    Saha, Kamalika.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Molecular biology.;Cellular biology.;Oncology.;Biochemistry.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 165 p.
  • 总页数 165
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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