Pardal R, Molofsky A V, He S, Morrison S J
Howard Hughes Medical Institute and Department of Internal Medicine, University of Michigan, Ann Arbor, 48109-0934, USA.
Cold Spring Harb Symp Quant Biol. 2005;70:177-85. doi: 10.1101/sqb.2005.70.057.
Networks of proto-oncogenes and tumor suppressors that control cancer cell proliferation also regulate stem cell self-renewal and possibly stem cell aging. Proto-oncogenes promote regenerative capacity by promoting stem cell function but must be balanced with tumor suppressor activity to avoid neoplastic proliferation. Conversely, tumor suppressors inhibit regenerative capacity by promoting cell death or senescence in stem cells. For example, the polycomb family proto-oncogene, Bmi-1, is consistently required for the self-renewal of diverse adult stem cells, as well as for the proliferation of cancer cells in the same tissues. Bmi-1 promotes stem cell self-renewal partly by repressing the expression of Ink4a and Arf, tumor suppressor genes that are commonly deleted in cancer. Despite ongoing Bmi-1 expression, Ink4a expression increases with age, potentially reducing stem cell frequency and function. Increased tumor suppressor activity during aging therefore may partly account for age-related declines in stem cell function. Thus, networks of proto-oncogenes and tumor suppressors have evolved to coordinately regulate stem cell function throughout life. Imbalances within such networks cause cancer or premature declines in stem cell activity that resemble accelerated aging.
控制癌细胞增殖的原癌基因和肿瘤抑制基因网络，也调节干细胞的自我更新，并可能影响干细胞衰老。原癌基因通过促进干细胞功能来提升再生能力，但必须与肿瘤抑制活性保持平衡，以避免肿瘤性增殖。相反，肿瘤抑制基因通过促进干细胞死亡或衰老来抑制再生能力。例如，多梳家族原癌基因Bmi-1，对于多种成体干细胞的自我更新以及同一组织中癌细胞的增殖都是持续必需的。Bmi-1部分通过抑制Ink4a和Arf的表达来促进干细胞自我更新，Ink4a和Arf是肿瘤抑制基因，在癌症中通常会缺失。尽管Bmi-1持续表达，但Ink4a的表达会随着年龄增长而增加，这可能会降低干细胞频率和功能。因此，衰老过程中肿瘤抑制活性的增加可能部分解释了与年龄相关的干细胞功能下降。所以，原癌基因和肿瘤抑制基因网络已经进化为在整个生命过程中协调调节干细胞功能。这些网络内的失衡会导致癌症或干细胞活性过早下降，类似于加速衰老。
