Differential regulation of Krüppel-like factor family transcription factor expression in neonatal rat cardiac myocytes: Effects of endothelin-1, oxidative stress and cytokines

Abstract

Krüppel-like transcription factors (Klfs) modulate fundamental cell processes. Cardiac myocytes are terminally-differentiated, but hypertrophy in response to stimuli such as endothelin-1. H2O2 or cytokines promote myocyte apoptosis. Microarray studies of neonatal rat myocytes identified several Klfs as endothelin-1-responsive genes. We used quantitative PCR for further analysis of Klf expression in neonatal rat myocytes. In response to endothelin-1, Klf2 mRNA expression was rapidly increased (∼ 9-fold; 15–30 min) with later increases in expression of Klf4 and Klf6 (∼ 5-fold; 30–60 min). All were regulated as immediate early genes (cycloheximide did not inhibit the increases in expression). Klf5 expression was increased at 1–2 h (∼ 13-fold) as a second phase response (cycloheximide inhibited the increase). These increases were transient and attenuated by U0126. H2O2 increased expression of Klf2, Klf4 and Klf6, but interleukin-1β or tumor necrosis factor α downregulated Klf2 expression with no effect on Klf4 or Klf6. Of the Klfs which repress transcription, endothelin-1 rapidly downregulated expression of Klf3, Klf11 and Klf15. The dynamic regulation of expression of multiple Klf family members in cardiac myocytes suggests that, as a family, they are actively involved in regulating phenotypic responses (hypertrophy and apoptosis) to extracellular stimuli.

Krüppel-like factor 4 regulates adaptive expression of the zinc transporterZip4in mouse small intestine

“…These changes may occur via KLF4, but that connection has not been directly investigated. Similarly, since KLF4 may regulate the p53 gene and oxidative stress (6,9,34), the upregulation of this transcription factor by zinc depletion could influence these processes. In addition, KLF4 has three zinc fingers (25); hence, DNA binding activity by this transcription factor could be sensitive to intracellular zinc levels.…”

The mammalian zinc finger transcription factor Krüppel‐like factor 3 (KLF3/BKLF)

“…Further understanding will be dependent on defining the FHL3-binding motif and examining changes in gene expression in KLF3 null cell lines, rescued with KLF3 protein in which this site has been mutated. The high level of expression of FHL3 in skeletal and cardiac muscle and recent reports linking KLF3 with muscle cell growth and differentiation (28,29), hints that common targets may be found in this tissue. Apart from the conserved CtBP-binding motif, KLF3 shares little N-terminal homology with KLF8 and KLF12, suggesting that the association with FHL3 may not be shared with KLF3's most closely related family members.…”

“…KLFs are known to play several roles in muscle cell development (46), and it has been shown that in cardiac myocytes, expression of KLF3 changes rapidly in response to stimuli leading either to hypertrophy or apoptosis (29). KLF3 has also recently been identified as a transcriptional regulator of skeletal muscle differentiation (28).…”

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

“…5,6 Later, it was found in a variety of other tissues, such as thymus, cornea, cardiac myocytes and lymphocytes. [7][8][9][10] KLF4 has an important role in the development and cell differentiation. 6,11,12 In normal lung tissue, KLF4 is expressed in fibroblasts and airway epithelial cells, and was found to be the most significantly altered lung gene at birth.…”