Pim-2是作為一種絲氨酸/蘇氨酸激酶于1984年首次被發(fā)現(xiàn)的,，與癌細(xì)胞幸存和生長作用有關(guān)。之前的研究表明,，高水平的PIM-2與各種惡性腫瘤緊密相關(guān),。
在人類細(xì)胞中，PIM-2的轉(zhuǎn)錄產(chǎn)物主要是兩種蛋白異構(gòu)體,，它們的大小分別是34及41kDa,。實(shí)驗(yàn)發(fā)現(xiàn)，它們都有相同的催化位點(diǎn),，但是蛋白質(zhì)的N端卻不同,。
近日，以色列希伯來大學(xué)的研究人員發(fā)現(xiàn)在所有測試的細(xì)胞系中,，34kDa的PIM-2異構(gòu)體在細(xì)胞核及細(xì)胞質(zhì)里有不同的構(gòu)型,。
為了深入研究這種34kDa的PIM-2異構(gòu)體在細(xì)胞內(nèi)的作用，研究人員將N端有HA標(biāo)簽的這種異構(gòu)體短暫表達(dá)于HeLa細(xì)胞,。結(jié)果卻導(dǎo)致了停滯在G1期的細(xì)胞以及凋亡細(xì)胞水平增加,。但是這樣的結(jié)果在有Flag標(biāo)簽的41kDa異構(gòu)體的實(shí)驗(yàn)中沒有獲得。
G1停滯及凋亡作用,，與CDK2 T14/Y15磷酸化的增加及蛋白酶體依賴的CDC25A的下調(diào),，與p57, E2F-1及p73上調(diào)密切相關(guān)。然而,，對激酶失活（kinase-dead）的有HA標(biāo)簽的34kDa PIM-2的過表達(dá)并沒有發(fā)現(xiàn)這樣的作用效果,。
在p73沉默的細(xì)胞使用p73顯性抑制，或者是過表達(dá)34kDa的PIM-2,，都表明了這些細(xì)胞周期停滯及凋亡作用都是p73依賴的,。
該研究表明，雖然PIM-2能夠作為一個有效的存活因子,，但是它在特定的環(huán)境下也能表現(xiàn)出原癌基因的作用,。相關(guān)論文發(fā)表在4月10日的PLoS ONE。（生物谷Deepblue編譯）
doi: 10.1371/journal.pone.0034736
PMC:
PMID:
Activation of Cell Cycle Arrest and Apoptosis by the Proto-Oncogene Pim-2
Daphna Levy, Ateret Davidovich, Shahar Zirkin, Yulia Frug, Amos M. Cohen, Sara Shalom, Jeremy Don.
Potent survival effects have been ascribed to the serine/threonine kinase proto-oncogene PIM-2.Elevated levels of PIM-2 are associated with various malignancies.In human cells, a single Pim-2 transcript gives rise mainly to two protein isoforms (34, 41 kDa) that share an identical catalytic site but differ at their N-terminus, due to in-frame alternative translation initiation sites.In this study we observed that the 34 kDa PIM-2 isoform has differential nuclear and cytoplasmic forms in all tested cell lines, suggesting a possible role for the balance between these forms for PIM-2's function.To further study the cellular role of the 34 kDa isoform of PIM-2, an N-terminally HA-tagged form of this isoform was transiently expressed in HeLa cells. Surprisingly, this resulted in increased level of G1 arrested cells, as well as of apoptotic cells.These effects could not be obtained by a Flag-tagged form of the 41 kDa isoform.The G1 arrest and apoptotic effects were associated with an increase in T14/Y15 phosphorylation of CDK2 and proteasom-dependent down-regulation of CDC25A, as well as with up-regulation of p57, E2F-1, and p73. No such effects were obtained upon over-expression of a kinase-dead form of the HA-tagged 34 kDa PIM-2.By either using a dominant negative form of p73, or by over-expressing the 34 kDa PIM-2 in p73-silenced cells, we demonstrated that these effects were p73-dependent.These results demonstrate that while PIM-2 can function as a potent survival factor, it can, under certain circumstances, exhibit pro-apoptotic effects as well.
