Identification and characterization of Grainyhead‐like epithelial transactivator (GET‐1), a novel mammalian Grainyhead‐like factor

Abstract

LMO-4 is an LIM-only factor that is highly expressed in many epithelial cells, including those of the epidermis and hair follicles. Because LMOs may function by interacting with DNA-binding proteins, we have used the yeast two-hybrid system to screen mouse skin libraries for LMO-4 -interacting DNA-binding proteins. In this screen, we isolated a novel LMO-4 -interacting factor highly related to the Drosophila gene Grainyhead. Grainyhead is epidermally expressed and carries out important functions in cuticular formation in the fly embryo. With the identification of this novel mammalian Grainyhead-like gene, referred to as Grainyhead-like epithelial transactivator 1 (GET-1), the known members of the mammalian Grainyhead-like gene family are extended to six, falling into two classes based on sequence homology. Of interest, the expression pattern of GET-1 is similar to that of Drosophila Grainyhead with highest expression in the somatic ectoderm/epidermis, but GET-1 is additionally expressed in epithelial cells of gastrointestinal, genitourinary, and respiratory tracks. The GET-1 protein localizes to the nucleus and binds to at least one Grainyhead DNA-binding site. The GET-1 DNA-binding domain maps to a region containing homology to the Drosophila Grainyhead DNA-binding domain. GET-1 homodimerizes in solution by means of a short C-terminally located domain that is homologous to other Grainyhead-like genes. A short domain located between amino acids 100 and 190, which bears no homology to known transactivation domains, is sufficient to confer transactivation to the heterologous GAL4 DNA-binding domain. In addition, GET-1 appears to contain repression domains consistent with the observation that Grainyhead and other mammalian Grainyhead-like genes can act both as activators and repressors. These data suggest that GET-1 is a transcriptional regulator that may perform important functions in epithelial tissues of mammals. Developmental Dynamics 226:604 -617, 2003.

Gene trap screening as an effective approach for identification of Wnt‐responsive genes in the mouse embryo

“…In vertebrates, this family consists of several members, including CRTR-1 (known as LBP-9 in human; Huang and Miller, 2000), CP2 (also known as LBP-1c and LSF; Lim et al, 1992;Shirra et al, 1994), NF2d9 (known as LBP-1a in human; Sueyoshi et al, 1995;Yoon et al, 1994), mammalian Grainyhead (MGR), brother of MGR (BOM; Wilanowski et al, 2002), sister of MGR (SOM)/GET1 (Kudryavtseva et al, 2003;Ting et al, 2003b), but their developmental roles have been largely unknown (Ramamurthy, 2001;Ting et al, 2003a). We found that CRTR-1 was specifically expressed in the ductal epithelium of the kidney and the salivary glands (Fig.…”

LMO4 can interact with Smad proteins and modulate transforming growth factor-β signaling in epithelial cells

“…We and others have found that LMO4 can interact with distinct DNA-binding proteins expressed at these locations (Sugihara et al, 1998;Sum et al, 2002;Kudryavtseva et al, 2003;Manetopoulos et al, 2003). As LMO4 is highly expressed at multiple sites of mesenchymal-epithelial interactions, it is attractive to propose that LMO4 interacts with and modulates the function of DNA-binding proteins in conserved signaling pathways involved in mesenchymal-epithelial signaling.…”

Expression of LMO4 and outcome in pancreatic ductal adenocarcinoma

“…Several LMO4-interacting proteins have been identified, including the ubiquitous nuclear adaptor protein Lbd1 (Grutz et al, 1998), the transcription factor deformed epidermal autoregulatory factor 1 (Sugihara et al, 1998), the basic helix-loop-helix protein HEN1 (Manetopoulos et al, 2003) and the grainyhead-like epithelial transactivator (Kudryavtseva et al, 2003), as well as the cofactor CtIP and BRCA1.…”