MIF family members cooperatively inhibit p53 expression and activity.
MIF family members cooperatively inhibit p53 expression and activity.
复制标题
DOI：
10.1371/journal.pone.0099795
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Mitchell RA
中科院分区：
文献类型：
--
作者：
Brock SE;Rendon BE;Xin D;Yaddanapudi K;Mitchell RA
肿瘤抑制因子 p53 由正常细胞和转化细胞中的基因毒性应激诱导，并在转录上协调细胞周期检查点控制和程序性细胞死亡反应。巨噬细胞迁移抑制因子 (MIF) 是一种自分泌和旁分泌作用的细胞因子/生长因子，可促进肺腺癌细胞运动、贴壁依赖性和新血管生成潜力。最近的几项研究表明，MIF 唯一已知的同源物 D-多巴色素互变异构酶（D-DT - 也称为 MIF-2）与 MIF 具有功能冗余活性，并协同促进 MIF 依赖性促肿瘤发生表型。我们现在报道，MIF 和 D-DT 协同抑制人肺腺癌细胞系中的稳态 p53 磷酸化、稳定性和转录活性。与单独丢失 MIF 或 D-DT 相比，siRNA 导致 MIF 和 D-DT 的联合丢失会导致细胞周期进程、贴壁独立性、病灶形成显着减少，并增加程序性细胞死亡。重要的是，p53 突变体和 p53 缺失的肺腺癌细胞系仅名义上免受 MIF/D-DT 联合缺陷的细胞生长影响，表明 p53 在这些转化的细胞生长表型中仅发挥次要作用。最后，发现 p53 激活增加与 MIF/D-DT 缺陷导致的异常激活的 AMP 激活蛋白激酶 (AMPK) 无关，但依赖于介导这些细胞中异常 AMPK 激活的活性氧 (ROS)。综合起来，这些发现表明 p53 野生型和突变型人肺腺癌肿瘤都依赖 MIF 家族成员来实现最大的细胞生长和存活。
The tumor suppressor p53 is induced by genotoxic stress in both normal and transformed cells and serves to transcriptionally coordinate cell cycle checkpoint control and programmed cell death responses. Macrophage migration inhibitory factor (MIF) is an autocrine and paracrine acting cytokine/growth factor that promotes lung adenocarcinoma cell motility, anchorage-independence and neo-angiogenic potential. Several recent studies indicate that the only known homolog of MIF, D-dopachrome tautomerase (D-DT - also referred to as MIF-2), has functionally redundant activities with MIF and cooperatively promotes MIF-dependent pro-tumorigenic phenotypes. We now report that MIF and D-DT synergistically inhibit steady state p53 phosphorylation, stabilization and transcriptional activity in human lung adenocarcinoma cell lines. The combined loss of MIF and D-DT by siRNA leads to dramatically reduced cell cycle progression, anchorage independence, focus formation and increased programmed cell death when compared to individual loss of MIF or D-DT. Importantly, p53 mutant and p53 null lung adenocarcinoma cell lines were only nominally rescued from the cell growth effects of MIF/D-DT combined deficiency suggesting only a minor role for p53 in these transformed cell growth phenotypes. Finally, increased p53 activation was found to be independent of aberrantly activated AMP-activated protein kinase (AMPK) that occurs in response to MIF/D-DT-deficiency but is dependent on reactive oxygen species (ROS) that mediate aberrant AMPK activation in these cells. Combined, these findings suggest that both p53 wildtype and mutant human lung adenocarcinoma tumors rely on MIF family members for maximal cell growth and survival.
登录
查看更多内容
影响因子：
5.7
作者：
Rosengren, E;Bucala, R;Rorsman, H
通讯作者：
Rorsman, H
DOI：
10.1084/jem.190.10.1375
发表时间：
1999-11-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hudson JD;Shoaibi MA;Maestro R;Carnero A;Hannon GJ;Beach DH
通讯作者：
Beach DH
DOI：
10.4049/jimmunol.181.4.2330
发表时间：
2008-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Coleman AM;Rendon BE;Zhao M;Qian MW;Bucala R;Xin D;Mitchell RA
通讯作者：
Mitchell RA
影响因子：
4.4
作者：
Abe, R;Peng, T;Metz, CN
通讯作者：
Metz, CN
影响因子：
11.4
作者：
Nemajerova, Alice;Mena, Patricio;Petrenko, Oleksi
通讯作者：
Petrenko, Oleksi