Petrenko Oleksi, Moll Ute M
Department of Pathology, Health Science Center, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
Mol Cell. 2005 Jan 21;17(2):225-36. doi: 10.1016/j.molcel.2004.11.052.
Macrophage migration inhibitory factor (MIF) is implicated in the regulation of inflammation and cell growth. We previously showed that MIF is a potent modulator of p53- and E2F-dependent pathways that are activated in response to oncogenic signaling. Here, we characterize the functional link between MIF and E2F transcription factors. Our results demonstrate that MIF-deficient cells exhibit E2F-dependent growth alterations and reduced susceptibility to oncogenic transformation. The basis for this transformation resistance is a perturbed function of the C-terminal Rb binding region of E2F4. However, inactivation of Rb or substitution of the E2F4 C-terminal domain by the E2F1 C-terminal region rescues the transformation defect. Importantly, the involvement of E2F factors in DNA replication rather than in regulation of transcription determines their oncogenic properties in the context of MIF deficiency. A proinflammatory molecule interfering with tumor suppression and DNA replication provides a compelling molecular link for the association of chronic inflammation and tumorigenesis.
巨噬细胞移动抑制因子（MIF）参与炎症调节和细胞生长。我们之前表明，MIF是p53和E2F依赖性途径的强效调节剂，这些途径在致癌信号响应中被激活。在此，我们描述了MIF与E2F转录因子之间的功能联系。我们的结果表明，缺乏MIF的细胞表现出E2F依赖性生长改变以及对致癌转化的敏感性降低。这种转化抗性的基础是E2F4 C末端Rb结合区域的功能紊乱。然而，Rb的失活或用E2F1 C末端区域替代E2F4 C末端结构域可挽救转化缺陷。重要的是，在MIF缺乏的情况下，E2F因子参与DNA复制而非转录调节决定了它们的致癌特性。一种干扰肿瘤抑制和DNA复制的促炎分子为慢性炎症与肿瘤发生之间的关联提供了令人信服的分子联系。
