細胞核中儲存著許多的遺傳訊息，掌管著真核生物所有的細胞活性。細胞核的型態以及結構基本上都保持恆定，除非細胞進行分裂，才會有劇烈的變化。但是這個特性不適用在腫瘤細胞中，因為細胞核的增大以及變形在癌細胞中很常見並且是判斷癌細胞的要件之一。在我們先前對於一AAA (ATPase associated with diverse cellular activities) ATPase，TER94的研究中，我們發現表現dominant-negative mutant TER94K2A在果蠅的感光細胞中(R細胞)，會使得細胞核異常的增大。這個結果特別的奇妙，因為這些R細胞是已經分化完全並且不會再進行細胞分裂，稱之為post-mitotic的細胞。我們發現維持細胞核大小以及結構需要TER94在細胞核中進行某些功能。為了瞭解TER94功能異常造成細胞核變大的機轉，我們進行了基因篩選並且發現p53可能參與在細胞核異常增大的過程中，p53的基因敲落可以回復TER94K2A過度表現所造成的細胞核異常增大現象。除此之外，mdm2的果蠅同源物corp擁有幫助p53降解的功能，而corp的過度表現也可以抑制細胞核的增大現象，和之前的結果吻合。P53調控很多的生理活性，透過和SREBP合作，他調控著脂質的生物合 成，而因為SREBP基因敲落也抑制細胞核增大現象，我們認為脂質的異常生合成會造成此現象。另外，PCNA是一個DNA複製的指標，在PCNA的染色中我們發現細胞核增大的R細胞內PCNA的訊號明顯增加，表示身為post-mitotic的R細胞可能因為TER94的功能異常而錯誤的重新進入了細胞週期。以上的實驗結果顯示TER94可能擁有一個新的機轉控制p53以及其下游的脂質生合成，此研究將有助於我們了解癌症的發生機制。

The nucleus houses genetic information to control essentially every aspect of eukaryotic cell activities. The morphology/structure of this organelle is rather stable in general unless the cell is undergoing the division. However, this remark obviously is not applicable in some neoplastic cells in which the increased nuclear size and deformed structure are standard prognostic parameters of cancer. In our previous study of TER94 AAA-ATPase, we found the expression of a dominant-negative mutant TER94K2A in fly photoreceptor cells (R cell) would cause an aberrant nuclear enlargement. This finding is especially intriguing because these R cells are at the end-dividing, postmitotic state. We find that maintaining nuclear size/structure requires TER94 function inside the nucleus. To understand the underlying mechanism of TER94 dysfunction-mediated nuclear expansion, we carried out a genetic screen and identified p53 as a potent modifier in this process. Genetic knockdown of p53 rescues TER94K2A-mediated nucleus enlargement. In agree with this, overexpression of Corp, the fly Mdm2 which antagonize p53 activity, also suppresses the nuclear phenotype. The aberrant nuclear expansion may result from an irregular lipid biosynthesis because the knockdown of SREBP, a partner of p53 in controlling lipid metabolic genes, also suppresses TER94K2A phenotype. To our surprise, we have observed the R cells bearing enlarged nuclei also stained positive for a DNA synthesis marker PCNA, suggesting those postmitotic cells may mistakenly re-enter the cell cycle due to TER94 loss of function. Together, these results point to a novel regulatory mechanism of nuclear TER94 in constraining the master cell cycle protein p53 and its downstream lipid metabolism and may shed light on tumorigenesis.

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