Kruppel-like factor 4 is involved in cell scattering induced by hepatocyte growth factor

Advance Online Publication August 1, 2012 doi: 10.1242/?jcs.108910 Jun-Kai Lai, Han-Chung Wu, Yuh-Chiang Shen, Hsin-Ying Hsieh, Shu-Yi Yang and Chia-Che Chang*?*: Corresponding author: Chia-Che Chang, Ph.D.
, Institute of Biomedical Sciences, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung 40227, TAIWAN; E-mail: chia_che{at}dragon.nchu.edu.tw; Tel: +886-4-22852022; Fax: +886-4-22853469 Hepatocyte growth factor/scatter factor (HGF) is unique by inducing epithelial cell scattering, a cellular event pivotal to HGF-mediated invasive-growth response essential for embryonic development and metastasis. Krüppel-like factor 4 (KLF4) is a multifunctional zinc-finger transcription factor involved in cell proliferation, differentiation and self-renewal. We herein present the first evidence for the functional connection between KLF4 and HGF-induced cell scattering. Particularly, we found that KLF4 was up-regulated by HGF in two independent epithelial cellular systems HepG2 and MDCK, whereas KLF4 knockdown inhibited HGF-induced E-cadherin suppression and cell scattering. Moreover, enforced nuclear KLF4 expression alone was sufficient to up-regulate KLF4, down-regulate E-cadherin and trigger scattering. Chromatin immunoprecipitation (ChIP) analysis further revealed that KLF4 induced suppression of E-cadherin transcription by directly binding to the E-cadherin promoter. Additionally, we proved that HGF-induced up-regulation of KLF4 transcription and cell scattering require activation of the MEK/ERK signaling pathway and the induction of early growth response 1 (EGR-1). At the mechanistic level, ChIP analysis validated a direct binding of EGR-1 to the KLF4 promoter for inducing KLF4 transcription; in turn, EGR-1-induced KLF4 binds to its own promoter, thus creating a positive feedback mechanism to sustain KLF4 expression and resultant cell scattering. Collectively, we conclude that KLF4 up-regulation by HGF represents a novel mechanism to mediate HGF-induced cell scattering and perhaps other associated events such as cell migration and invasion.

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Autophagy and cell growth - the yin and yang of nutrient responses

Advance Online Publication May 30, 2012 doi: 10.1242/?jcs.103333 May 15, 2012 J Cell Sci 125, 2359-2368. Thomas P. Neufeld?

Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA neufeld{at}med.umn.edu As a response to nutrient deprivation and other cell stresses, autophagy is often induced in the context of reduced or arrested cell growth. A plethora of signaling molecules and pathways have been shown to have opposing effects on cell growth and autophagy, and results of recent functional screens on a genomic scale support the idea that these processes might represent mutually exclusive cell fates. Understanding the ways in which autophagy and cell growth relate to one another is becoming increasingly important, as new roles for autophagy in tumorigenesis and other growth-related phenomena are uncovered. This Commentary highlights recent findings that link autophagy and cell growth, and explores the mechanisms underlying these connections and their implications for cell physiology and survival. Autophagy and cell growth can inhibit one another through a variety of direct and indirect mechanisms, and can be independently regulated by common signaling pathways. The central role of the mammalian target of rapamycin (mTOR) pathway in regulating both autophagy and cell growth exemplifies one such mechanism. In addition, mTOR-independent signaling and other more direct connections between autophagy and cell growth will also be discussed.

Key words This article is part of a Minifocus on Autophagy. For further reading, please see related articles: ‘Ubiquitin-like proteins and autophagy at a glance’ by Tomer Shpilka et al. (J. Cell Sci. 125, 2343-2348) and ‘Autophagy and cancer – issues we need to digest’ by Emma Liu and Kevin Ryan (J. Cell Sci. 125, 2349-2358).

Funding

The work of our laboratory is supported by the National Institutes of Health [grant number GM62509]. Deposited in PMC for release after 12 months.

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