Biology of Krüppel‐like factor 6 transcriptional regulator in cell life and death

Abstract

SummaryAn essential role for the Krü ppel-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, Krü ppel-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.

Kruppel-like Transcription Factor 6 Regulates Inflammatory Macrophage Polarization

“…Alterations in KLF6 expression or function have been implicated in the pathogenesis of numerous human diseases, including cancer, hepatic steatosis, and hepatic fibrosis (13). Previous studies have also linked this factor to hematopoietic biology (20).…”

“…Kruppel-like factor 6 (KLF6) is a member of the zinc finger family of transcription factors that regulate key cellular processes such as development, differentiation, proliferation, and programmed cell death (13). Recent studies have linked Kruppel-like factors (KLFs) to the biology of macrophage activation and polarization (14,15).…”

MiR-181a Regulates Blood-Tumor Barrier Permeability by Targeting Krüppel-Like Factor 6

“…16 It has a more generalized role in tumorigenenesis as a tumor suppressor gene that is inactivated in a number of human cancers including glioma. 17 In addition, KLF6 has been shown to have a role in EC motility.…”

Cytokine amplification and macrophage effector functions in aortic inflammation and abdominal aortic aneurysm formation

“…KLF6 is a zinc finger transcription factor belonging to a 17-member family of DNA binding transcriptional regulators initially described as a tumor suppressor gene (9)(10)(11)(12), but currently recognized as having multiple, diverse roles during differentiation and development with the capacity to act both as an activator and a repressor of transcription. KLF6 is essential for early hematopoiesis and vasculogenesis since whole-body KLF6 deletion leads to failure of both events and death in utero (13).…”