title: Genome-wide pathway analysis reveals different signaling pathways between secreted lactoferrin and intracellular delta-lactoferrin.
abstract: Human lactoferrin (LF) is a multifunctional protein involved in immunomodulation, cellular growth, and differentiation. In addition to its secreted form (sLF), an alternative form (ΔLF) lacking the signal sequence has been found to be downregulated in cancer. Although the signaling pathways mediated by LF have been studied in a few cell models, there have been no relevant systemic approaches. Therefore, this study was carried out to identify and compare signaling networks provoked by the two LF isoforms. For this, the two forms were overexpressed in HEK293 cells using the Flp-In T-Rex system, after which genome-wide expression analysis of 18,367 genes was conducted. Pathway analysis of the genes showing altered expression identified pathways which are responsible for cell survival and apoptosis. In addition, the pathways mediated by the two LF forms were within distantly related networks. GPCR, PI3K complex, and POU5F1, which are involved in receptor-mediated pathways, were centered in the sLF network, whereas RIF1, NOS3, and RNPS1, which are involved in intracellular signaling, were centered in the ΔLF network. These results suggest that structural differences between the LF isoforms, mainly glycosylation, determine the fate of LF signaling. Furthermore, these findings provide information relating to the role of ΔLF which is downregulated during carcinogenesis.
authors: Department of Life Science, Dongguk University-Seoul, Seoul, Korea.
authors: Byungtak
authors: B
authors: Kim
authors: Seongeun
authors: S
authors: Kang
authors: Sun Jung
authors: SJ
authors: Kim
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D007781:Lactoferrin / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D034501:Telomere-Binding Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; C084538:RNPS1 protein, human; D012261:Ribonucleoproteins; C492743:Rif1 protein, human; D034501:Telomere-Binding Proteins; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D048051:p38 Mitogen-Activated Protein Kinases; D007781:Lactoferrin
references: Int J Cancer. 2005 Mar 20;114(2):299-306
references: 15543612
references: Biochem Cell Biol. 2012 Jun;90(3):307-19
references: 22320386
references: Hum Mol Genet. 2002 Jan 1;11(1):93-105
references: 11773003
references: Cell Mol Life Sci. 2005 Nov;62(22):2549-59
references: 16261255
references: Development. 2005 Dec;132(23):5137-45
references: 16251211
references: J Biol Chem. 2001 Nov 9;276(45):42575-9
references: 11535608
references: Biochem Mol Biol Int. 1997 Sep;43(1):79-87
references: 9315285
references: RNA. 2011 Jan;17(1):145-54
references: 21098140
references: Biochimie. 2009 Jan;91(1):109-22
references: 18725266
references: Nucleic Acids Res. 2007;35(13):4542-51
references: 17586820
references: Blood. 1992 Jul 1;80(1):235-40
references: 1535239
references: Eur J Biochem. 2004 Jan;271(2):303-17
references: 14717698
references: Nature. 2005 Oct 13;437(7061):1032-7
references: 16136080
references: FEBS J. 2007 Apr;274(8):2038-53
references: 17371504
references: Oncol Rep. 2011 Oct;26(4):965-70
references: 21725617
references: Mol Cells. 1998 Oct 31;8(5):530-6
references: 9856339
references: Antiviral Res. 2001 Dec;52(3):225-39
references: 11675140
references: Biochem Cell Biol. 2002;80(1):95-102
references: 11908649
references: Cell Mol Life Sci. 2005 Nov;62(22):2560-75
references: 16261254
references: Mol Cell Biol. 2004 Feb;24(3):1174-87
references: 14729963
references: Biochem Cell Biol. 2006 Jun;84(3):282-90
references: 16936798
references: Int J Oncol. 2011 Apr;38(4):933-9
references: 21274508
references: Cell Signal. 2010 Aug;22(8):1185-92
references: 20227494
references: Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2198-203
references: 9122171
references: Carcinogenesis. 2009 Aug;30(8):1314-9
references: 19483192
references: Leukemia. 2011 Jul;25(7):1211-3
references: 21468036
references: Cancer Lett. 2006 Nov 18;243(2):145-59
references: 16530325
references: Biometals. 2004 Jun;17(3):225-9
references: 15222469
references: Mol Cells. 2009 Jul 31;28(1):37-42
references: 19533041
references: Mol Cell Biol. 2007 Nov;27(21):7718-26
references: 17785435
references: PLoS One. 2011;6(6):e21599
references: 21738726
references: Brain Res. 2004 Dec 10;1029(1):34-40
references: 15533313
references: Mol Cancer Ther. 2011 Apr;10(4):580-90
references: 21282360
references: Biochem Biophys Res Commun. 2005 Nov 11;337(1):330-6
references: 16188236
references: FEBS J. 2010 May;277(9):2051-66
references: 20345905
references: Br J Cancer. 2010 Mar 2;102(5):883-91
references: 20160723
references: Biochimie. 2009 Jan;91(1):102-8
references: 18534198
references: Int Immunol. 2009 Oct;21(10):1185-97
references: 19692539
references: Crit Rev Oncog. 2006 Dec;12(3-4):171-203
references: 17425502
references: J Cell Biol. 2009 Nov 2;187(3):385-98
references: 19948482
references: EMBO J. 1999 Aug 16;18(16):4560-70
references: 10449421
references: Pigment Cell Melanoma Res. 2011 Feb;24(1):207-18
references: 20880198
references: Osteoarthritis Cartilage. 2010 Jan;18(1):117-25
references: 19747587