長(zhǎng)期以來,，研究人員已經(jīng)知道，細(xì)胞內(nèi)質(zhì)網(wǎng)（ER）的功能障礙與多種人類疾病甚至癌癥有關(guān),，但是,，人們對(duì)內(nèi)質(zhì)網(wǎng)在正常細(xì)胞變形初期中的作用還知之甚少。
來自美國(guó)密歇根大學(xué),、加州大學(xué)舊金山分校等機(jī)構(gòu)的研究人員利用原始的人類黑色素細(xì)胞和人類痣組織切片,，證實(shí)由分子腫瘤基因誘導(dǎo)產(chǎn)生的內(nèi)質(zhì)網(wǎng)壓力程度可以揭示出衰老（senescence）的活化機(jī)制。 這項(xiàng)研究成果發(fā)表在9月10日出版的Nature Cell bioogy雜志上,。
另外,，研究人員發(fā)現(xiàn)HRASG12V的癌癥發(fā)生形式（而不是它的下游靶標(biāo)BRAF）參與一種迅速的細(xì)胞周期停滯，這種停滯與ER的大面積真空和擴(kuò)張有關(guān),。
但是,，抑癌基因p53和p16這兩種典型的凋亡標(biāo)記物都不能解釋黑色素細(xì)胞對(duì)HRASG12V的特殊反應(yīng)。相反,，HRASG12V驅(qū)動(dòng)的細(xì)胞衰老是由內(nèi)質(zhì)網(wǎng)相關(guān)未折疊蛋白質(zhì)應(yīng)答（UPR）所控制的,。
HRAS對(duì)UPR的影響是有選擇性的。這些結(jié)果揭示出衰老（premature senescence）并不是對(duì)活化癌基因的一個(gè)協(xié)同機(jī)制,，并且支持了內(nèi)質(zhì)網(wǎng)是腫瘤控制的一個(gè)“守門員”的直接功能,。
實(shí)際上，這并不奇怪,，生物谷專家很早就注意到內(nèi)質(zhì)網(wǎng)在細(xì)胞中的一系列功能,，尤其是細(xì)胞凋亡的發(fā)生。見：
內(nèi)質(zhì)網(wǎng)與細(xì)胞凋亡
內(nèi)質(zhì)網(wǎng)應(yīng)激參與胰島素抵抗和糖尿病的發(fā)病
原始出處：
Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway
Christophe Denoyelle, George Abou-Rjaily, Vladimir Bezrookove, Monique Verhaegen, Timothy M. Johnson, Douglas R. Fullen, Jenny N. Pointer, Stephen B. Gruber, Lyndon D. Su, Mikhail A. Nikiforov, Randal J. Kaufman, Boris C. Bastian & Maria S. Soengas
Published online: 10 September 2006 | doi:10.1038/ncb1471
Dysfunction of the endoplasmic reticulum (ER) has been reported in a variety of human pathologies, including cancer. However, the contribution of the ER to the early stages of normal cell transformation is largely unknown. Using primary human melanocytes and biopsies of human naevi (moles), we show that the extent of ER stress induced by cellular oncogenes may define the mechanism of activation of premature senescence. Specifically, we found that oncogenic forms of HRAS (HRASG12V) but not its downstream target BRAF (BRAFV600E), engaged a rapid cell-cycle arrest that was associated with massive vacuolization and expansion of the ER. However, neither p53, p16INK4a nor classical senescence markers – such as foci of heterochromatin or DNA damage – were able to account for the specific response of melanocytes to HRASG12V. Instead, HRASG12V-driven senescence was mediated by the ER-associated unfolded protein response (UPR). The impact of HRAS on the UPR was selective, as it was poorly induced by activated NRAS (more frequently mutated in melanoma than HRAS). These results argue against premature senescence as a converging mechanism of response to activating oncogenes and support a direct role of the ER as a gatekeeper of tumour control.
