Proliferating cell nuclear antigen ( PCNA )的表現，常被用為細胞增生之指標，但是當細胞進行DNA修補時，PCNA也會表現。P21最早被發現可抑制細胞週期的進行，但近來的研究則顯示p21在某些生長訊息的刺激下，對細胞週期的進行亦有正向的調節作用。雌性動物之子宮及陰道受到卵巢激素的影響，會有週期性的增生，分化與死亡現象，因此它提供一個良好的動物模式，來探討PCNA與p21之表現和細胞增生與死亡之關係。本論文首先使用正常動情週期之大白鼠來探討PCNA表現與細胞進行增生、凋亡之關聯性。實驗結果顯示，在proestrus時期，管腔上皮細胞有很強的PCNA表現而無凋亡的細胞出現，進入estrus時期，PCNA幾乎不表現，並有大量凋亡的細胞出現，可見在大白鼠之動情週期中PCNA之表現與細胞生長有很好的相關性。
我們也利用去卵巢小鼠進行實驗來探討p21及PCNA的表現與子宮和陰道細胞進行增生、凋亡之關聯性。小鼠去卵巢後兩星期，將去除卵巢之小鼠分為兩組，一組自背部皮下植入雌二醇膠囊; 另外一組則給予雌二醇膠囊處理三天，然後將其移除。在不同時間點將動物犧牲取其子宮與陰道利用組織免疫化學染色法分析PCNA及p21之表現並利用TUNEL來偵測凋亡之細胞。為了研究組織之DNA合成及無mitotic index，在犧牲動物前5小時和3小時分別打入bromodeoxyuridine ( BrdU ) 和colchicine。我們的結果顯示去除卵巢的小鼠經由雌二醇作用後，子宮上皮細胞內PCNA、cyclin D1、cyclin A、p21的表現、BrdU incorporation 及mitotic index都會增加。利用免疫螢光染色的方法我們也發現，上皮細胞表現p21的時間較BrdU incorporation及PCNA的表現晚。在雌二醇作用下，陰道上皮細胞的層數增加，同時在基底層( basal layer )的陰道上皮細胞內PCNA、p21及BrdU incorporation之表現增加。此外利用雙重免疫螢光染色可檢測出，子宮與陰道上皮細胞有共同表現BrdU與PCNA的細胞，但表現BrdU之上皮細胞並不表現p21。這些結果顯示p21的表現可能與上皮細胞增生無關。另外在雌二醇移除之小鼠，子宮上皮細胞亦發現有細胞凋亡，BrdU incorporation，PCNA與p21之表現。雌二醇移除後會表現PCNA，p21及BrdU incorporation的陰道上皮細胞數目隨時間增加而逐漸減少。
綜合上述結果得知，在雌二醇刺激下，子宮與陰道上皮細胞PCNA的表現大致與BrdU及mitotic index等細胞增生之marker相符，但雌二醇移除後引起子宮組織萎縮的過程，PCNA也有表現，它的出現並不一定與細胞增生有關。不論雌二醇存在與否，p21都可以在生殖道之表皮細胞表現，而且其表現之時間與組織內分布之位置， 這些結果顯示p21在子宮及陰道可能擔任細胞週期抑制蛋白的角色。

The expression of proliferating cell nuclear antigen ( PCNA ) is frequently used as cell proliferation marker. However, it is also expressed in other conditions not related to growth, such as DNA repair. P21 was originally identified as an inhibitor of cell cycle. Recent evidences also suggested that it could act as a positive regulator of cell cycle under the influence of growth stimulators. The growth, differentiation and apoptosis of uterine and vaginal epithelia are regulated by ovarian steroids during reproductive cycle. It provides a good model to study the expression of PCNA and p21 during cell growth and death. In this study, the expression of PCNA and apoptosis in rat uterus during estrus cycle was investigated. The expression of PCNA was obvious in uterine epithelium and no apoptotic cells were detected at proestrus phase. However, the number of apoptotic cells increased and the expression of PCNA in epithelium decreased during estrus phase. It appears that in the rat model the PCNA expression is correlated well with cell proliferation during estrous cycle.
To clarify roles of PCNA and p21 in growth and death, the expression of p21 and PCNA in the uterus and vagina during tissue growth and regression was further investigated. Mice were ovariecomized for two weeks and then divided into two groups. One group received subcutaneous implantation of capsules containing 17β-estradiol (E2), and the other group received E2 capsules for three days and then their capsules were removed. The uteri and vagina were collected at various intervals for immunohistochemical staining of PCNA, p21 and for TUNEL analysis. To study DNA synthesis and mitotic index, bromodeoxyuridine ( BrdU ) and colchicine were injected into mice three and five hours before the sacrifice of animals. Our results showed that estrogen treatment increased mitotic index, BrdU incorporation, and the expressions of PCNA, cyclin D, cyclin A, and p21 in uterine epithelium. The expression of P21 was expressed later than that of PCNA and BrdU incorporation. In the vagina, estrogen treatment increased epithelial layers, stimulated BrdU incorporation, and PCNA and p21 expression in basal layer. In addition, BrdU incorporation occurred in PCNA positive cells but not in p21 positive cells both in uterine epithelium and vagina. These results suggested that the expression of p21 did not involve in cell proliferation. The withdrawal of estrogen from E2-treated mice induced apoptosis, BrdU incorporation, and the expression of PCNA and p21 in uterine epithelium. While, in the vagina, the expression of PCNA and p21 and the BrdU incorporation decreased in the absence of estrogen.
In conclusion, the expression of PCNA in the epithelia of uterus and vagina under the stimulation of estrogen coincided well with mitotic index and BrdU incorporation. However, PCNA was also expressed in the regressing tissues, indicating that the PCNA expression may not be soly correlated with cell proliferation. P21 can be expressed in the tissues of reproductive tract both in the presence or absence of estrogen. The temporal and spatial evidences from this study have suggested that p21 functions as a cell cycle inhibitor.

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