GH and Senescence: A New Understanding of Adult GH Action.
GH and Senescence: A New Understanding of Adult GH Action.
复制标题
DOI：
10.1210/jendso/bvab177
复制
发表时间：
2022-01-01
影响因子：
4.1
通讯作者：
Melmed S
中科院分区：
文献类型：
--
作者：
Chesnokova V;Melmed S
复制性衰老的发生是由于不能修复DNA损伤和p53/p21和p16 INK 4通路的激活。它被认为是阻止DNA损伤细胞增殖的预防机制。稳定衰老细胞的特征在于衰老相关分泌表型（SASP），其根据细胞类型产生并分泌细胞因子、趋化因子和/或基质金属蛋白酶。SASP蛋白可以增加细胞增殖，促进癌前转化为恶性肿瘤细胞，引发DNA损伤，并改变组织微环境。此外，衰老细胞随着年龄的增长而积累，从而加重与年龄相关的组织损伤。在这里，我们回顾了迄今为止未得到重视的作用，生长激素（GH）作为SASP的组成部分，自分泌和旁分泌的方式行事。在衰老细胞中，GH被DNA损伤诱导的p53激活，并抑制DNA修复蛋白ATM、Chk 2、p53和H2 AX的磷酸化。含有丰富的细胞内GH的生长激素腺瘤表现出增加的体细胞拷贝数改变，指示DNA损伤，并与诱导的p53/p21相关。由于这一途径抑制了DNA损伤细胞的增殖，这些机制可能是缓慢增殖的垂体生长激素腺瘤的衰老表型和良性性质的基础。在高度增殖的细胞中，如结肠上皮细胞，响应DNA损伤诱导的GH抑制p53，从而引发衰老细胞增殖。由于衰老细胞含有未修复的DNA损伤，GH可能使衰老细胞逃避衰老并重新进入细胞周期，导致获得有害突变。这些机制，至少部分，可能是在动物模型中观察到的GH和慢性GH水平升高的患者的促衰老作用的基础。
Replicative senescence occurs due to an inability to repair DNA damage and activation of p53/p21 and p16INK4 pathways. It is considered a preventive mechanism for arresting proliferation of DNA-damaged cells. Stably senescent cells are characterized by a senescence-associated secretory phenotype (SASP), which produces and secretes cytokines, chemokines, and/or matrix metalloproteinases depending on the cell type. SASP proteins may increase cell proliferation, facilitating conversion of premalignant to malignant tumor cells, triggering DNA damage, and altering the tissue microenvironment. Further, senescent cells accumulate with age, thereby aggravating age-related tissue damage. Here, we review a heretofore unappreciated role for growth hormone (GH) as a SASP component, acting in an autocrine and paracrine fashion. In senescent cells, GH is activated by DNA-damage-induced p53 and inhibits phosphorylation of DNA repair proteins ATM, Chk2, p53, and H2AX. Somatotroph adenomas containing abundant intracellular GH exhibit increased somatic copy number alterations, indicative of DNA damage, and are associated with induced p53/p21. As this pathway restrains proliferation of DNA-damaged cells, these mechanisms may underlie the senescent phenotype and benign nature of slowly proliferating pituitary somatotroph adenomas. In highly proliferative cells, such as colon epithelial cells, GH induced in response to DNA damage suppresses p53, thereby triggering senescent cell proliferation. As senescent cells harbor unrepaired DNA damage, GH may enable senescent cells to evade senescence and reenter the cell cycle, resulting in acquisition of harmful mutations. These mechanisms, at least in part, may underlie pro-aging effects of GH observed in animal models and in patients with chronically elevated GH levels.
登录
查看更多内容
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
--
作者：
Abbud, RA;Takumi, I;Melmed, S
通讯作者：
Melmed, S
影响因子：
18.2
作者：
Campisi J
通讯作者：
Campisi J
影响因子：
2.4
作者：
Greer, Kimberly A.;Canterberry, Sarah C.;Murphy, Keith E.
通讯作者：
Murphy, Keith E.
影响因子：
17.1
作者：
Guevara-Aguirre J;Balasubramanian P;Guevara-Aguirre M;Wei M;Madia F;Cheng CW;Hwang D;Martin-Montalvo A;Saavedra J;Ingles S;de Cabo R;Cohen P;Longo VD
通讯作者：
Longo VD