Departments of Cell and Developmental Biology and Information Service Research Computing Group, University of Massachusetts Medical School, Worcester, MA 01655, USA .
Cancer Res. 2013 Jun 1;73(11):3451-9. doi: 10.1158/0008-5472.CAN-12-3902. Epub 2013 Apr 22.
Notch signaling regulates a broad spectrum of cell fate decisions and differentiation. Both oncogenic and tumor suppressor functions have been shown for Notch signaling. However, little is known about the underlying mechanisms of its tumor suppressor function. Here, we report that expression of Notch3, a member of Notch family transmembrane receptors, was elevated in human cells during senescence activated by various senescence-inducing stimuli. This upregulation of Notch3 was required for the induction of p21 expression in senescent cells. Downregulation of Notch3 led to a delayed onset of senescence and extended replicative lifespan, whereas adventitious expression of Notch3 was sufficient to activate senescence and p21 expression. The ability of Notch3 to induce senescence and p21 expression was dependent on the canonical Notch singling. Deletion of p21 in cells significantly attenuated Notch3-induced senescence. Furthermore, a significant decrease in Notch3 expression was observed in human tumor cell lines as well as primary human breast cancer and melanoma samples compared with normal tissues. Restoration of Notch3 expression in human tumor cells resulted in inhibition of cell proliferation and activation of senescence. Collectively, our results reveal a novel function of Notch3 in senescence regulation and tumor suppression.
Notch 信号通路调节广泛的细胞命运决定和分化。 Notch 信号通路已被证明具有致癌和肿瘤抑制功能。然而，其肿瘤抑制功能的潜在机制知之甚少。在这里，我们报告 Notch 家族跨膜受体成员 Notch3 的表达在各种衰老诱导刺激激活的人细胞衰老过程中升高。 Notch3 的这种上调对于衰老细胞中 p21 表达的诱导是必需的。 Notch3 的下调导致衰老的延迟发生和复制寿命的延长，而 Notch3 的异位表达足以激活衰老和 p21 表达。 Notch3 诱导衰老和 p21 表达的能力依赖于经典的 Notch 信号通路。细胞中 p21 的缺失显著减弱了 Notch3 诱导的衰老。此外，与正常组织相比，人肿瘤细胞系以及原发性人乳腺癌和黑色素瘤样本中 Notch3 的表达明显降低。在人肿瘤细胞中恢复 Notch3 的表达导致细胞增殖的抑制和衰老的激活。总之，我们的结果揭示了 Notch3 在衰老调控和肿瘤抑制中的新功能。
