Epigen, the Last Ligand of ErbB Receptors, Reveals Intricate Relationships between Affinity and Mitogenicity

Kochupurakkal, Bose; Harari, Daniel; Di-Segni, Ayelet; Maik-Rachline, Galia; Lyass, Ljuba; Gur, Gal; Kerber, Gabriele; Citri, Ami; Lavi, Sara; Eilam, Raya; Chalifa‐Caspi, Vered; Eshhar, Zelig; Pikarsky, Eli; Pinkas‐Kramarski, Ronit; Bacus, Sarah; Yarden, Yosef

doi:10.1074/jbc.m413919200

Cited by 83 publications

(78 citation statements)

References 43 publications

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“…The earliest change in gene expression in the back skin of Fa2h Ϫ/Ϫ mice was the strong up-regulation of Epgn in the basal layer of the SG and in some adjacent cells of the ORS. Epgn is a low affinity EGF receptor/ErbB1 ligand but has high mitogenic activity because of its weak ability to induce ErbB receptor degradation (52). Dahlhoff et al (31) demonstrated a specific SG enlargement in Epgn-transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

Normal Fur Development and Sebum Production Depends on Fatty Acid 2-Hydroxylase Expression in Sebaceous Glands

Maier

Meixner

Hartmann

et al. 2011

Journal of Biological Chemistry

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2-Hydroxylated fatty acid (HFA)-containing sphingolipids are abundant in mammalian skin and are believed to play a role in the formation of the epidermal barrier. Fatty acid 2-hydroxylase (FA2H), required for the synthesis of 2-hydroxylated sphingolipids in various organs, is highly expressed in skin, and previous in vitro studies demonstrated its role in the synthesis of HFA sphingolipids in human keratinocytes. Unexpectedly, however, mice deficient in FA2H did not show significant changes in their epidermal HFA sphingolipids. Expression of FA2H in murine skin was restricted to the sebaceous glands, where it was required for synthesis of 2-hydroxylated glucosylceramide and a fraction of type II wax diesters. Absence of FA2H resulted in hyperproliferation of sebocytes and enlarged sebaceous glands during hair follicle morphogenesis and anagen (active growth phase) in adult mice. This was accompanied by a significant up-regulation of the epidermal growth factor receptor ligand epigen in sebocytes. Loss of FA2H significantly altered the composition and physicochemical properties of sebum, which often blocked the hair canal, apparently causing a delay in the hair fiber exit. Furthermore, mice lacking FA2H displayed a cycling alopecia with hair loss in telogen. These results underline the importance of the sebaceous glands and suggest a role of specific sebaceous gland or sebum lipids, synthesized by FA2H, in the hair follicle homeostasis.

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Section: Discussionmentioning

confidence: 99%

Normal Fur Development and Sebum Production Depends on Fatty Acid 2-Hydroxylase Expression in Sebaceous Glands

Maier

Meixner

Hartmann

et al. 2011

Journal of Biological Chemistry

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“…Also on chromosome 4, EPGN, EREG, and AREG encode epithelial growth factor (EGF)-like mitogens that stimulate MAP kinase signaling (Kochupurakkal et al 2005). Within the induced cluster on chromosome 1, two ephrin genes, EFNA4 and EFNA3, are AR-regulated.…”

Section: Primary Arg Clustersmentioning

confidence: 99%

Cell- and gene-specific regulation of primary target genes by the androgen receptor

Bolton¹,

So²,

Chaivorapol³

et al. 2007

Genes Dev.

309

273

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The androgen receptor (AR) mediates the physiologic and pathophysiologic effects of androgens including sexual differentiation, prostate development, and cancer progression by binding to genomic androgen response elements (AREs), which influence transcription of AR target genes. The composition and context of AREs differ between genes, thus enabling AR to confer multiple regulatory functions within a single nucleus. We used expression profiling of an immortalized human prostate epithelial cell line to identify 205 androgen-responsive genes (ARGs), most of them novel. In addition, we performed chromatin immunoprecipitation to identify 524 AR binding regions and validated in reporter assays the ARE activities of several such regions. Interestingly, 67% of our AREs resided within ∼50 kb of the transcription start sites of 84% of our ARGs. Indeed, most ARGs were associated with two or more AREs, and ARGs were sometimes themselves linked in gene clusters containing up to 13 AREs and 12 ARGs. AREs appeared typically to be composite elements, containing AR binding sequences adjacent to binding motifs for other transcriptional regulators. Functionally, ARGs were commonly involved in prostate cell proliferation, communication, differentiation, and possibly cancer progression. Our results provide new insights into cell-and gene-specific mechanisms of transcriptional regulation of androgen-responsive gene networks.[Keywords: Androgen receptor (AR); androgen response element (ARE); transcription; steroid receptor; chromatin immunoprecipitation (ChIP); prostate cancer] Supplemental material is available at http://www.genesdev.org.

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“…EGFR is a transmembrane glycoprotein with intrinsic tyrosine kinase activity that becomes activated after binding EGF family members, including EGF, heparin-binding EGF-like growth factor (HB-EGF), amphiregulin (AR), betacellulin (BTC), transforming growth factor-α (TGF-α), epiregulin (EPR) and epigen (Iwamoto and Mekada, 2006;Kochupurakkal et al, 2005). Osteoblast proliferation and differentiation are abnormal in mice lacking EGFR, and this leads to impaired bone formation and skeletal structure (Sibilia et al, 2003;Wang et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Potential Involvement of Twist2 and Erk in the Regulation of Osteoblastogenesis by HB-EGF-EGFR Signaling

Nakamura

Toita

Yoshimoto

et al. 2010

Cell Struct. Funct.

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ABSTRACT. Epidermal growth factor (EGF) family members play important roles in the skeletal system. In this study, we examined the role of EGF receptor (EGFR) signaling in osteoblastogenesis in vitro. The expression of HB-EGF and epiregulin (EPR) was transiently induced within 24 h after osteogenic stimulation, but when preosteoblastic MC3T3-E1 cells were incubated with HB-EGF or EPR, osteoblast differentiation was inhibited. These effects were Ras-dependent, and ERK modulated Runx2 activity through the localization of Smad1 and the induction of Twist2. PI3-kinase was also required for the induction of Twist2. However, the inhibition of individual signaling pathways was not sufficient to overcome HB-EGF-mediated inhibition of osteoblast differentiation. Additionally, HB-EGF treatment promoted the proliferation of preosteoblasts, and this was associated with the downregulation of p27 at the protein level. These results suggest that HB-EGF-EGFR signaling inhibits the differentiation of osteoblasts by suppression of Runx2 transcriptional activity and enhances proliferation of preosteoblasts by downregulation of expression of p27.

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Epigen, the Last Ligand of ErbB Receptors, Reveals Intricate Relationships between Affinity and Mitogenicity

Cited by 83 publications

References 43 publications

Normal Fur Development and Sebum Production Depends on Fatty Acid 2-Hydroxylase Expression in Sebaceous Glands

Normal Fur Development and Sebum Production Depends on Fatty Acid 2-Hydroxylase Expression in Sebaceous Glands

Cell- and gene-specific regulation of primary target genes by the androgen receptor

Potential Involvement of Twist2 and Erk in the Regulation of Osteoblastogenesis by HB-EGF-EGFR Signaling

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