Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
IUBMB Life. 2010 Dec;62(12):896-905. doi: 10.1002/iub.396.
An essential role for the Krüppel-like transcription factor family has been determined in the regulation of remarkable processes including cell proliferation, differentiation, signal transduction, oncogenesis, and cell death. A member of this group, Krüppel-like factor 6 (KLF6), identified on the basis of its ability to regulate a group of genes belonging to the carcinoembryonic antigen gene family, has been involved in human carcinogenesis. Early studies proposed a tumor suppressor function for KLF6 because of its ability to reduce cell proliferation through several biochemical mechanisms including regulation of cell cycle components, oncogene products, and apoptosis. Mutations within the klf6 gene, decreased expression and/or loss-of-heterozygosity were associated with the development of different human malignancies, and, hence, further supporting the tumor suppressor function of KLF6. This view has been challenged by other studies in distinct types of human cancers describing infrequent genetic alterations of klf6 gene or even enhanced expression in some tumors. The scenario about KLF6 function became still more complex as the description of oncogenic KLF6 splice variant 1 (SV1) with dominant negative activity against the wild type KLF6 (wtKLF6) protein. Additionally, increased evidence is suggesting that KLF6 is a bonafide target of several signaling cascades, which ultimate regulatory effect on this protein could drive decisions of cell life and death, facing the dilemma about how wtKLF6 could be involved in both processes. These apparently conflicting situations, emerged by apparently opposite effects mediated by wtKLF6, may be related, at least in part, to the biological cross-talk with the c-Jun oncoprotein. Depending on the stimulus received by the cell, wtKLF6 interaction with c-Jun determines different cell outcomes such as proliferation control or apoptosis. Thus, KLF6 responsiveness represents a kind of cell warning signal on receiving different stimuli, including oncogenic activation and microbial infections, orchestrating the implementation of proliferation and apoptotic programs.
Krüppel 样转录因子家族在细胞增殖、分化、信号转导、肿瘤发生和细胞死亡等显著过程的调节中起着至关重要的作用。该家族的一个成员，Krüppel 样因子 6（KLF6），因其能够调节一组属于癌胚抗原基因家族的基因而被识别，已参与人类肿瘤发生。早期的研究提出 KLF6 具有肿瘤抑制功能，因为它能够通过几种生化机制减少细胞增殖，包括调节细胞周期成分、癌基因产物和细胞凋亡。klf6 基因突变、表达降低和/或杂合性丢失与不同人类恶性肿瘤的发生有关，进一步支持 KLF6 的肿瘤抑制功能。然而，其他研究在不同类型的人类癌症中描述了 klf6 基因的遗传改变不频繁，甚至在一些肿瘤中表达增强，这一观点受到了挑战。随着具有显性负作用的致癌 KLF6 剪接变异体 1（SV1）的描述，KLF6 功能的情况变得更加复杂，该变异体能与野生型 KLF6（wtKLF6）蛋白发生相互作用。此外，越来越多的证据表明，KLF6 是几个信号通路的真正靶点，这些信号通路对该蛋白的最终调节作用可能会导致细胞生死的决定，这就引出了 wtKLF6 如何参与这两个过程的问题。wtKLF6 介导的这些明显矛盾的情况可能与 c-Jun 癌蛋白的生物学交叉有关。根据细胞接收到的刺激，wtKLF6 与 c-Jun 的相互作用决定了不同的细胞结果，如增殖控制或细胞凋亡。因此，wtKLF6 的反应性代表了细胞在接收到不同刺激时的一种警告信号，包括致癌激活和微生物感染，协调增殖和凋亡程序的执行。
