Pin1 是脯胺酸異構酶中，第一個被證明在酵母菌及哺乳類細胞中，與細胞分裂
相關。有趣的是，Pin1 對於G2 時期，扮演著負向調控之角色，而其機制仍不清楚。
此外，Pin1-WW domain 中Ser16 位點之磷酸化，其生理意義與細胞中哪一個激酶負
責此位點之磷酸化也尚未知道。在此研究，針對細胞週期G2/M 過渡期中，探討Pin1
Ser16 位點磷酸化與Aurora A/hBora 複合物調控細胞進入有絲分裂期之關係進行探
討。我們發現在G2 時期，GSK3β 能磷酸化hBora 於Ser274 及Ser278 兩個位點上，
其磷酸化可促進細胞進入有絲分裂期; 此外，Aurora A 可磷酸化Pin1 於Ser16 位點
上，其磷酸化能抑制Pin1 與其受質結合的功能，而降低Pin1 在G2/M 過渡期的功能。
有趣的是，hBora Ser274 及Ser278 的磷酸化位點，恰為Pin1 的結合位點。當過度表
現Pin1 於細胞中，Pin1 能戰勝細胞中Aurora A 對Pin1 的抑制結果，藉由結合hBora
而促使hBora 經由β-TrCP 而提早降解，導致Aurora A/hBora 複合物活化Plk1 之能力
下降，而延遲細胞進入有絲分裂期。而當細胞進入有絲分裂期時，抑制Pin1 表現或
活性，則會導致hBora 蛋白的累積而伴隨著有絲分裂進行的延遲，意味著Pin1 可以
回饋調控有絲分裂期中hBora 蛋白的降解，而確保有絲分裂期的進行及離開。總結而
言，此研究藉由探討Aurora A-Pin1-hBora-GSK3β 分子間的後轉譯修飾及交互作用，了解細胞如何調控進入以及離開有絲分裂期。
此外，當細胞受到損害，Pin1 能調控p53 的穩定性，並增加p53 在DNA 損害
下G2/M 檢查點之功能。Pin1 和Aurora A 已被報導過度表現於人類癌細胞當中，且
皆參與G2/M 過渡期的調控。而Pin1-Ser16 磷酸化的表現，在癌細胞中尚未被分析。
因此，Aurora A 造成Pin1-Ser16 之磷酸化，是否對於癌細胞中G2/M 檢查點功能之缺失，以及其是否與細胞易產生癌化之相關性，值得未來進一步探討。

Pin1 is the first prolyl isomerase to be identified that is involved in cell division in
both yeast and mammalian cells. Interestingly, the mechanism of Pin1 acts as a negative
regulator of mitotic activity in G2 remains unclear. Besides, the biological significant and
which kinase is responsible for Pin1-Ser16 phosphorylation in vivo also remain unknown.
In this study, the functional link of Ser16 phosphorylation with Aurora A/hBora
complex-mediated mitotic entry is investigated at the G2/M transition. We uncovered a
suppressed role of Pin1 in regulating Aurora A/hBora complex activity. GSK3β-mediated
Ser274 and Ser278 phosphorylation of hBora is involved in mitotic entry and that is
characterized as a novel Pin1 binding protein. Aurora A phosphorylates Pin1 at Ser16 and
suppresses Pin1 G2/M function to prevent the premature hBora degradation mediated
by β-TrCP, whereas Pin1 overexpression can override the suppressed role of Pin1 by
Aurora A and therefore delays mitotic entry. Furthermore, Pin1 depletion or inhibition
results in marked hBora accumulation and concomitant with delayed mitotic progression,
indicating that Pin1 feedback promotes hBora degradation in mitosis to ensure mitotic
progression and exit. In conclusion, the cell cycle progression control from mitotic entry to
exit is regulated by the post-translational modification and interaction of Aurora
A-Pin1-hBora-GSK3β axis.
Furthermore, when cells encounter stress, such as DNA damage, Pin1 can stabilize
p53 and increase p53-mediated G2/M checkpoint response. In addition, Pin1 and Aurora A
are overexpressed in human cancers and both of their function are related to G2/M
regulation. The status of Pin1-Ser16 phosphorylation has not yet been clarified in human
cancers. Accordingly, it is interesting to investigate whether Aurora A-mediated Pin1
III
Ser16 phosphorylation is associated with the impaired G2/M checkpoint response in
cancers and whether that can increase the susceptibility of cell transformation in the future.

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