The Snail signaling branch downstream of the TGF-β/Smad3 pathway mediates Rho activation and subsequent stress fiber formation.

Cancer cells acquire malignant phenotypes through an epithelial-mesenchymal transition, which is induced by environmental factors or extracellular signaling molecules, including transforming growth factor-β (TGF-β). Among epithelial-mesenchymal transition-associated cell responses, cell morphological changes and cell motility are closely associated with remodeling of the actin stress fibers. Here, we examined the TGF-β signaling pathways leading to these cell responses.

TGF-β-induced cell motility requires downregulation of ARHGAPs to sustain Rac1 activity.

Transforming growth factor-β (TGF-β) signaling promotes cancer progression. In particular, the epithelial-mesenchymal transition (EMT) induced by TGF-β is considered crucial to the malignant phenotype of cancer cells. Here, we report that the EMT-associated cellular responses induced by TGF-β are mediated by distinct signaling pathways that diverge at Smad3.

Dissociation of the AhR/ARNT complex by TGF-β/Smad signaling represses gene expression and inhibits benze[a]pyrene-mediated cytotoxicity.

Cytochrome P450 1A1 (CYP1A1) catalyzes the metabolic activation of polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (B[a]P) and is transcriptionally regulated by the aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) complex upon exposure to PAHs. Accordingly, inhibition of CYP1A1 expression reduces production of carcinogens from PAHs. Although transcription of the gene is known to be repressed by transforming growth factor-β (TGF-β), how TGF-β signaling is involved in the suppression of gene expression has yet to be clarified.

A comparative analysis of Smad-responsive motifs identifies multiple regulatory inputs for TGF-β transcriptional activation.

Smad proteins are transcriptional regulators activated by TGF-β. They are known to bind to two distinct Smad-responsive motifs, namely the Smad-binding element (SBE) (5'-GTCTAGAC-3') and CAGA motifs (5'-AGCCAGACA-3' or 5'-TGTCTGGCT-3'). However, the mechanisms by which these motifs promote Smad activity are not fully elucidated.

Maid is a negative regulator of transforming growth factor-β-induced cell migration.

Maternal Id-like molecule (Maid) is a dominant negative helix-loop-helix protein that has been implicated in regulating gene expression as well as cell-cycle progression. Overexpressed Maid was previously shown to inhibit certain cellular responses induced by transforming growth factor-β (TGF-β), such as TGF-β-induced cytostasis and cell motility, but not epithelial-mesenchymal transition (EMT). The role of endogenous Maid in regulating TGF-β signalling, however, has not been elucidated.

Epithelial splicing regulatory proteins 1 (ESRP1) and 2 (ESRP2) suppress cancer cell motility via different mechanisms.

ESRP1 (epithelial splicing regulatory protein 1) and ESRP2 regulate alternative splicing events associated with epithelial phenotypes of cells, and both are down-regulated during the epithelial-mesenchymal transition. However, little is known about their expression and functions during carcinogenesis. In this study, we found that expression of both ESRP1 and ESRP2 is plastic: during oral squamous cell carcinogenesis, these proteins are up-regulated relative to their levels in normal epithelium but down-regulated in invasive fronts.

Oligodendrocyte transcription factor 1 (Olig1) is a Smad cofactor involved in cell motility induced by transforming growth factor-β.

Transforming growth factor (TGF)-β plays crucial roles in embryonic development and adult tissue homeostasis by eliciting various cellular responses in target cells. TGF-β signaling is principally mediated through receptor-activated Smad proteins, which regulate expression of target genes in cooperation with other DNA-binding transcription factors (Smad cofactors). In this study, we found that the basic helix-loop-helix transcription factor Olig1 is a Smad cofactor involved in TGF-β-induced cell motility.

PSK2 coordinates glucose metabolism and utilization to maintain ultradian clock-coupled respiratory oscillation in Saccharomyces cerevisiae yeast.

Ultradian clock-coupled respiratory oscillation (UCRO) in an aerobic continuous culture of Saccharomyces cerevisiae S288C is principally regulated by control of certain redox reactions of energy metabolism. It is also modulated by the metabolism of storage carbohydrates during adaptation to environmental change. However, the mechanism of cell sensing and response to environmental nutrients in UCRO is unknown.

Importance of polarisome proteins in reorganization of actin cytoskeleton at low pH in Saccharomyces cerevisiae.

The actin cytoskeleton of the yeast Saccharomyces cerevisiae can be altered rapidly in response to external cues. We reported previously that S. cerevisiae responds to low-pH stress by transiently depolarizing its actin cytoskeleton, and that this step requires a mitogen-activated protein kinase, high osmolarity glycerol 1 (Hog1p).

Low pH facilitates uptake of proteins by cells through a non-endocytic pathway.

We previously noted that bovine apolipoprotein A-II (apoA-II) had a bactericidal effect causing morphological changes in the cytoplasm. To determine whether and how apoA-II and apoA-I, which have acidic isoelectric points (pIs), enter cells, we determined the rates of uptake of FITC-labeled proteins by fibroblast cells and found that they entered cells more easily at low pH than at neutral pH under conditions where endocytosis was inhibited. The enhanced uptake of proteins at low pH was also observed for other proteins examined regardless of the molecular weight (M(r)) or pI in a time-dependent manner, although the efficiency of uptake varied among the proteins.

Structure-activity analysis of an antimicrobial peptide derived from bovine apolipoprotein A-II.

We previously showed that bovine apolipoprotein A-II (apoA-II) has antimicrobial activity against Escherichia coli in PBS, and its C-terminal residues 49-76 are responsible for the activity using synthetic peptides. In order to understand the structural requirements of peptide 49-76 for the antimicrobial activity, the N- or C-terminus was truncated and then the charged (Lys or Asp) or Ser residues were replaced by Ala. Deletion of the first or last three amino acids and replacement of Lys-54/55 or 71/72 by Ala caused a substantial decreases in alpha-helical content in 50% TFE, showing the possible presence of helices in N- and C-terminal regions, respectively.