Nuclear Factor Kappa B (NF-κB) in Inflammation

Heparin binding epidermal growth factor-like growth factor (HB-EGF) is involved in development and homeostasis as well as in pathological processing of chronic diseases, especially cancer. Enhancement of HB-EGF expression is directly or indirectly regulated by transcriptional factors, including activator protein-1 (AP-1), specificity protein (SP)1, SP3, nuclear factor kappa B (NF-κB), hypoxia inducible factor 1, alpha subunit (HIF-1α, myogenic differentiation 1 (MyoD), Wilms tumor 1 (WT-1) and snail homolog 1 (Snail), and also by microRNAs. These transcription or posttranscription factors may communicate to form an autocrine HB-EGF amplification loop. Emerging evidence has indicated that HB-EGF is a rational target for the therapy of cancer and atherosclerosis. In this review, we discuss the relationship between the HB-EGF autocrine loop and HB-EGF transcriptional factors, and we highlight HB-EGF as a therapeutic target in diverse diseases. The epidermal growth factor receptor family of receptor tyrosine kinases is composed of four members in mammals; ERBB1/HER1 (also EGFR), ERBB2/HER-2, ERBB3/HER3 and ERBB4/HER-4 (1, 2). There are several ERBB-specific ligands that can be categorized into three groups depending on receptor binding specificity. The first group includes epidermal growth factor (EGF), amphiregulin (AREG), and transforming growth factor alpha (TGF-α), which all bind specifically to ERBB1. The second group includes betacellulin (BTC), heparin-binding EGF-like growth factor (HB-EGF) and epiregulin (EREG), which all exhibit dual specificity for ERBB1 and ERBB4. The third group includes neuregulin (NRG), which binds to ERBB3 or ERBB4 (3). ERBB1-mediated intracellular signaling controls many of the functions required for growth, migration and proliferation (4). The activation of ERBB1 through binding to its ligands transmits signals for cell growth [dependent on the Kirsten rat sarcoma viral oncogene (Ras)v-raf-1 murine leukemia viral oncogene homolog 1 (Raf)-extracellular signal-regulated kinases (ERK) pathway], cell survival [dependent on the phosphoinositide-3-kinase (PI3K) v-akt murine thymoma viral oncogene homolog 1 (AKT) pathway], and transcriptional control [dependent on signal transducer and activator of transcription 3 (Stat3)]. Activated ERBB1 forms a heterodimer complex with other ERBBs or other receptors, resulting in a variety of different signals. ERBB1 ligands, which are located on the cell membrane, are proteolytically cleaved and released upon action of various stimuli, including growth factors, cytokines, ultraviolet light, hypoxia and anticancer agents. HB-EGF, an ERBB1 ligand, is synthesized as a transmembrane precursor (pro-HB-EGF) that can serve as a juxtacrine growth factor. ERBB1 transactivation is induced by a soluble form of HB-EGF through ectodomain shedding in a paracrine manner. In lipid metabolism and cancer progression, HB-EGF expression is up-regulated in an autocrine manner. This means that HB-EGF is a promising target for the therapy of cancer and atherosclerosis (5, 6). Thus, it is plausible that HB-EGF contributes to diverse biological events through its own amplification loop via unique transcriptional control. In this review, we focus on the relationship between HB-EGF expression and transcription factors through the autocrine loop. Nuclear Factor Kappa B (NF-κB) in Inflammation HB-EGF is a 22 kDa protein that can be purified from conditioned medium, in which macrophage-like U-937 cells have been cultured (7). Initial reports suggested that pro2347 Correspondence to: Shingo Miyamoto, MD, Ph.D., Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. Tel: +81 928011011, Fax: +81 928654114, e-mail: [email protected]