长期以来，研究人员已经知道，细胞内质网（ER）的功能障碍与多种人类疾病甚至癌症有关，但是，人们对内质网在正常细胞变形初期中的作用还知之甚少。
来自美国密歇根大学、加州大学旧金山分校等机构的研究人员利用原始的人类黑色素细胞和人类痣组织切片，证实由分子肿瘤基因诱导产生的内质网压力程度可以揭示出衰老（senescence）的活化机制。 这项研究成果发表在9月10日出版的Nature Cell bioogy杂志上。
另外，研究人员发现HRASG12V的癌症发生形式（而不是它的下游靶标BRAF）参与一种迅速的细胞周期停滞，这种停滞与ER的大面积真空和扩张有关。
但是，抑癌基因p53和p16这两种典型的凋亡标记物都不能解释黑色素细胞对HRASG12V的特殊反应。相反，HRASG12V驱动的细胞衰老是由内质网相关未折叠蛋白质应答（UPR）所控制的。
HRAS对UPR的影响是有选择性的。这些结果揭示出衰老（premature senescence）并不是对活化癌基因的一个协同机制，并且支持了内质网是肿瘤控制的一个“守门员”的直接功能。
实际上，这并不奇怪，生物谷专家很早就注意到内质网在细胞中的一系列功能，尤其是细胞凋亡的发生。见：
内质网与细胞凋亡
内质网应激参与胰岛素抵抗和糖尿病的发病
原始出处：
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.
