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研究生:王敦正
研究生(外文):Tsun-Cheng Wang
論文名稱:乳癌磷酸酶(Brk)與HaCaT細胞分化關係之研究
論文名稱(外文):On the relationship between breast tumor kinase (Brk) and HaCaT cells differentiation
指導教授:陳瑞華陳瑞華引用關係
指導教授(外文):Ruey-Hwa Chen
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:英文
論文頁數:75
中文關鍵詞:乳癌磷酸酶角質細胞分化間接免疫螢光染色細胞培養
外文關鍵詞:Breast tumor kinaseHaCaT cellsKeratinocyte differentiationFilaggrinK10Indirect immunofluorescence
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皮膚角質細胞的分化過程十分微妙精細,牽涉到許多生化反應之調控。蛋白質酪胺酸磷酸化現象是其中已知的一種重要反應,目前證實有一些受體與非受體型蛋白質酪胺酸磷酸化激酶參與這個過程。乳癌磷酸酶是新近由轉移的乳癌組織中分離出來的一種非受體型蛋白質酪胺酸磷酸化激酶,目前已知與部分腫瘤生成及上皮細胞分化有關。過去有研究指出在老鼠身上的乳癌磷酸酶同系物Sik會參與角質細胞的分化過程,因此我們的研究主題延伸為乳癌磷酸酶在人體皮膚生理上的角色為何。從不同種類的皮膚切片組織化學染色與體外培養HaCaT細胞間接免疫螢光染色結果顯示,乳癌磷酸酶主要分布在基底細胞層以上的角質細胞中。同時於細胞質與細胞核中均可見其蹤跡。雖然鈣離子濃度改變會影響角質細胞分化,不過在HaCaT細胞中並不會影響分化標記與乳癌磷酸酶的表現;然而讓HaCaT細胞長時間在培養皿中生長至十分緻密的情況下時,不但可以誘發分化現象,且伴隨乳癌磷酸酶的訊息核糖核酸與蛋白質表現量明顯增加。值得注意的是,在無血清培養情況下,乳癌磷酸酶的表現量反而被抑制下來,不過HaCaT細胞在此時仍可以持續進行分化過程,因此兩者未必受到共同調控。與原始細胞相較,含轉殖乳癌磷酸酶基因與激酶功能喪失型基因的細胞,在皮膚分化標記的表現量上,並無顯著差異。另外,在整體細胞的含磷酸化酪胺酸蛋白質表徵上,我們發現到一個特殊的約70kDa大小的訊號,出現在含轉殖乳癌磷酸酶基因的細胞溶解物中。乳癌磷酸酶與人類皮膚分化及其他生理現象的關係,仍有待進一步的研究。

Differentiation of epidermal keratinocytes is a complex process involving simultaneously turning on or turning off multiple biochemical reactions. Tyrosine phosphorylation is one of the well defined events during keratinocytes differentiation. Many protein tyrosine kinases have been found to play important roles. Breast tumor kinase (Brk), a non-receptor protein tyrosine kinase initially identified from metastatic breast tumor, exhibits dual functions both in tumorigenesis and differentiation. Based on a previous report that its mouse orthologue, Sik, is involved in keratinocyte differentiation, we focuses on Brk in human aspects. The results of histochemical staining of various cutaneous specimens and indirect immunofluorescence of cultured HaCaT cells demonstrated that Brk is expressed exclusively in suprabasal keratinocytes. The subcellular localization of Brk is both cytoplasmic and intranuclear. Although manipulating extracellular calcium concentration can regulate the differentiation of cultured human and mouse primary keratinocytes, we found that Brk is insensitive to calcium concentration in the culture medium. Using prolonged confluence of HaCaT cells as an in vitro keratinocytes differentiation model, we found both the mRNA and protein levels of Brk can be up-regulated, and that this regulation is serum-dependent. Under serum free conditions, the differentiation markers can still be up-regulated while the expression of Brk is suppressed, indicating both are not necessarily co-regulated. Preliminary data did not show significant variations in differentiation markers among the prototype cells and the stably transfected cells either with intact Brk cDNA or its kinase-dead mutant. A yet to be determined 70 kD band was found in the total cellular phosphotyrosine profile of Brk overexpressed cells. Further studies are needed to clarify mutual relationships between Brk and keratinocytes differentiation.

CONTENTS 1
BENCH DAYS 3
ABSTRACT 4
中文摘要 5
INTRODUCTION 6
Overview of keratinocyte differentiation 6
Tyrosine phosphorylation and keratinocyte differentiation 8
Origin, function, and current understandings about Brk 9
Aims of this study 11
MATERIALS AND METHODS 14
Antibodies, chemicals, and reagents 14
Histochemical staining 14
Cells and culture reagents 15
Establishment of stable cell lines 15
Measurement of calcium concentration in mediums 16
Northern blotting 16
Protein extraction 17
Western blotting 17
Indirect immunofluorescence of monolayer cultured cells 18
RESULTS 20
Brk is detected exclusively in the suprabasal epidermal layers 20
HaCaT cells can express differentiation markers via confluence 21
Brk shows a suprabasal enhancement pattern in differentiated HaCaT cells 23
Brk can be upregulated via confluence, and this induction is serum dependent 24
Overexpression of Brk and a kinase-dead mutant (KM) in HaCaT cells 26
Effects on differentiation 26
Effects on phosphotyrosine profile 27
DISCUSSION 28
Distribution of Brk in the skin 28
Subcellular localization of Brk 30
Induction of HaCaT cells differentiation 32
Brk and HaCaT cells differentiation 35
Upregulation of Brk in suprabasal HaCaT cells 35
Confluence induced, serum dependent Brk expression 36
Influence of Brk on keratinocytes physiology 37
Epilogue and future works 38
REFERENCES 41
TABLES 51
Table I Peptides regulators of keratinocytes physiology 51
Table II Comparison of HaCaT cells and primary keratinocytes 52
Table III Benign and malignant skin specimens analyzed for Brk expression 53
Table IV Induction of in vitro differentiation of HaCaT cells 54
FIGURES 55
Fig. 1 Concepts of keratinocytes differentiation 55
Fig. 2 Structures of cytoplasmic tyrosine kinase. 56
Fig. 3 Suprabasal location of Brk in the epidermis 57
Fig. 4 Brk in benign and malignant skin tumors. 58
Fig. 5 Brk in BCC-1/KMC and MCF10A cell lines 59
Fig. 6 Brk and melanocytes 60
Fig. 7 Morphologies of HaCaT vells in various culture conditions 61
Fig. 8 Confluence induced K10 expression. 62
Fig. 9 Calcium shift and filaggrin expression 63
Fig. 10 Brk localization in HaCaT cells cultured in low calcium medium. 64
Fig. 11 Suprabasal enhancement pattern of Brk 65
Fig. 12 Solitary suprabasal enhancement cell 66
Fig. 13 Confluence/serum can up-regulate Brk’s expression 67
Fig. 14 Stability of Brk transcript 68
Fig. 15 Calcium shift and Brk 68
Fig. 16 De-differentiation and Brk 68
Fig. 17 Establishment of stable Brk and KM cell lines 68
Fig. 18 Influence of Brk and KM on HaCaT keratinocytes differentiation. 68
Fig. 19 Dissociation of Brk expression with keratinocytes differentiation 68
Fig. 20 Influence of calcium and confluence on Brk, K10, and filaggrin expression. 68
Fig. 21 Phosphotyrosine profiles of HaCaT, Brk, and KM cells 68

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