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| | The IER3 protein contains several potential ERK phosphorylation sites - one functionally verified on Thr18 (P) (Garcia et al., 2002), a PEST like sequence a functional nuclear localization sequence (NLS) (Kruse et al., 2005), a potential transmembrane domain (TM) and a N-linked glycosylation site (NLG). |
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| Description | IER3 as well as its rodent homologues PRG1 and gly96 consists of 156, 160 and 153 amino acids, respectively, and, to current knowledge, share no significant sequence similarities with any other known protein. IER3 shuttles between the cytoplasm and the nucleus (Kruse et al., 2005) where it accumulates in promyelocytic nuclear dots, unique structures that are involved in stress response. IER3 is also localized in the mitochondrial membrane where it interferes with the ATP producing system (Shen et al., 2009). |
| Expression | Epithelial cells, keratinocytes, hepatocytes, monocytes, lymphocytes. |
| Localisation | Nucleus, mitochondrial membrane, cytoplasm. |
| Function | Immediate early gene X-1 (IEX-1), also known as IER3/DIF2, is a growth and stress associated early response gene (Kondratyev et al., 1996; Schäfer et al., 1996) involved in a great variety of cellular functions (Wu, 2003). The expression of IER3 is under control of many stimuli and cellular conditions including growth factors, cytokines, viral infection, UV- and gamma-irradiation or biomechanical strain. Recent data demonstrated that IER3 modulates cell cycle progression and proliferation, as well as programmed cell death in a cell type- and stimulus-dependent fashion (Wu, 2003).
A line of functional studies revealed that IER3 exerts a dual role in cellular growth control and apoptosis. For example, in epithelial cells, hepatocytes and keratinocytes IER3 enhances apoptosis (Schilling et al., 2001; Arlt et al., 2007; Arlt et al., 2008; Sebens Muerkoster et al., 2008) whereas in hematological precursor cells and in immune cells IER3 rather favours cellular survival and differentiation (Wu, 2003; Mittal et al., 2006; Rocher et al., 2007; Rocher et al., 2007).
Recent studies revealed that IER3 expression is inversely related to the formation of malignant tumors such as colon cancer (Nambiar et al., 2004; Sebens Muerkoster et al., 2008), pancreatic cancer (Sasada et al., 2008) and endocrine tumors (Dilley et al., 2005), thus pointing to a tumor suppressive potential of IER3. Obviously, the cellular actions of IER3 are complex depending on cell type and context related conditions but one mechanism by which IER3 could affect cellular viability is the negative interference with NF-kappaB activation. To some extent this action of IER3 relies on the dampening of IkappaB degradation thereby leading to a reduced nuclear localization of NF-kappaB (Arlt et al., 2001; Arlt et al., 2003; Arlt et al., 2007).
Moreover, a recent study demonstrated that IER3 is also capable to directly bind to leading to the inhibition of p65-dependent gene transcription (Arlt et al., 2008). Thus, IER3 is supposed to be part of a NF-kappaB dependent counterregulatory mechanism that might be particularly relevant in the control of immune responses.
Consequently, an impaired NF-kappaB control may promote severe inflammatory processes and carcinogenesis. |
| Homology | None. |
| Identification and characterization of a radiation-inducible glycosylated human early-response gene. |
| Kondratyev AD, Chung KN, Jung MO. |
| Cancer Res. 1996 Apr 1;56(7):1498-502. |
| PMID 8603392 |
| |
| PRG1: a novel early-response gene transcriptionally induced by pituitary adenylate cyclase activating polypeptide in a pancreatic carcinoma cell line. |
| Schafer H, Trauzold A, Siegel EG, Folsch UR, Schmidt WE. |
| Cancer Res. 1996 Jun 1;56(11):2641-8. |
| PMID 8653710 |
| |
| IEX-1L, an apoptosis inhibitor involved in NF-kappaB-mediated cell survival. |
| Wu MX, Ao Z, Prasad KV, Wu R, Schlossman SF. |
| Science. 1998 Aug 14;281(5379):998-1001. |
| PMID 9703517 |
| |
| The putative apoptosis inhibitor IEX-1L is a mutant nonspliced variant of p22(PRG1/IEX-1) and is not expressed in vivo. |
| Schafer H, Arlt A, Trauzold A, Hunermann-Jansen A, Schmidt WE. |
| Biochem Biophys Res Commun. 1999 Aug 19;262(1):139-45. |
| PMID 10448082 |
| |
| Expression of the NF-kappa B target gene IEX-1 (p22/PRG1) does not prevent cell death but instead triggers apoptosis in Hela cells. |
| Arlt A, Grobe O, Sieke A, Kruse ML, Folsch UR, Schmidt WE, Schafer H. |
| Oncogene. 2001 Jan 4;20(1):69-76. |
| PMID 11244505 |
| |
| IEX-1, an immediate early gene, increases the rate of apoptosis in keratinocytes. |
| Schilling D, Pittelkow MR, Kumar R. |
| Oncogene. 2001 Nov 29;20(55):7992-7. |
| PMID 11753682 |
| |
| IEX-1: a new ERK substrate involved in both ERK survival activity and ERK activation. |
| Garcia J, Ye Y, Arranz V, Letourneux C, Pezeron G, Porteu F. |
| EMBO J. 2002 Oct 1;21(19):5151-63. |
| PMID 12356731 |
| |
| The early response gene IEX-1 attenuates NF-kappaB activation in 293 cells, a possible counter-regulatory process leading to enhanced cell death. |
| Arlt A, Kruse ML, Breitenbroich M, Gehrz A, Koc B, Minkenberg J, Folsch UR, Schafer H. |
| Oncogene. 2003 May 22;22(21):3343-51. |
| PMID 12761504 |
| |
| Roles of the stress-induced gene IEX-1 in regulation of cell death and oncogenesis. |
| Wu MX. |
| Apoptosis. 2003 Jan;8(1):11-8. |
| PMID 12510147 |
| |
| Genetic signatures of high- and low-risk aberrant crypt foci in a mouse model of sporadic colon cancer. |
| Nambiar PR, Nakanishi M, Gupta R, Cheung E, Firouzi A, Ma XJ, Flynn C, Dong M, Guda K, Levine J, Raja R, Achenie L, Rosenberg DW. |
| Cancer Res. 2004 Sep 15;64(18):6394-401. |
| PMID 15374946 |
| |
| Global gene expression in neuroendocrine tumors from patients with the MEN1 syndrome. |
| Dilley WG, Kalyanaraman S, Verma S, Cobb JP, Laramie JM, Lairmore TC. |
| Mol Cancer. 2005 Feb 3;4(1):9. |
| PMID 15691381 |
| |
| Immediate early gene X1 (IEX-1) is organized in subnuclear structures and partially co-localizes with promyelocytic leukemia protein in HeLa cells. |
| Kruse ML, Arlt A, Sieke A, Grohmann F, Grossmann M, Minkenberg J, Folsch UR, Schafer H. |
| J Biol Chem. 2005 Jul 1;280(26):24849-56. Epub 2005 Apr 26. |
| PMID 15855159 |
| |
| NF-kappaB-dependent regulation of the timing of activation-induced cell death of T lymphocytes. |
| Mittal A, Papa S, Franzoso G, Sen R. |
| J Immunol. 2006 Feb 15;176(4):2183-9. |
| PMID 16455974 |
| |
| Immediate early gene-X1 interferes with 26 S proteasome activity by attenuating expression of the 19 S proteasomal components S5a/Rpn10 and S1/Rpn2. |
| Arlt A, Minkenberg J, Kruse ML, Grohmann F, Folsch UR, Schafer H. |
| Biochem J. 2007 Mar 1;402(2):367-75. |
| PMID 17107344 |
| |
| Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity. |
| Rocher G, Letourneux C, Lenormand P, Porteu F. |
| J Biol Chem. 2007 Feb 23;282(8):5468-77. Epub 2007 Jan 2. |
| PMID 17200115 |
| |
| IEX-1 directly interferes with RelA/p65 dependent transactivation and regulation of apoptosis. |
| Arlt A, Rosenstiel P, Kruse ML, Grohmann F, Minkenberg J, Perkins ND, Folsch UR, Schreiber S, Schafer H. |
| Biochim Biophys Acta. 2008 May;1783(5):941-52. Epub 2007 Dec 23. |
| PMID 18191642 |
| |
| Prognostic significance of the immediate early response gene X-1 (IEX-1) expression in pancreatic cancer. |
| Sasada T, Azuma K, Hirai T, Hashida H, Kanai M, Yanagawa T, Takabayashi A. |
| Ann Surg Oncol. 2008 Feb;15(2):609-17. Epub 2007 Nov 17. |
| PMID 18026799 |
| |
| The apoptosis-inducing effect of gastrin on colorectal cancer cells relates to an increased IEX-1 expression mediating NF-kappa B inhibition. |
| Sebens Muerkoster S, Rausch AV, Isberner A, Minkenberg J, Blaszczuk E, Witt M, Folsch UR, Schmitz F, Schafer H, Arlt A. |
| Oncogene. 2008 Feb 14;27(8):1122-34. Epub 2007 Aug 20. |
| PMID 17704804 |
| |
| IEX-1 targets mitochondrial F1Fo-ATPase inhibitor for degradation. |
| Shen L, Zhi L, Hu W, Wu MX. |
| Cell Death Differ. 2009 Apr;16(4):603-12. Epub 2008 Dec 19. |
| PMID 19096392 |
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