title: Progranulin (granulin/epithelin precursor) and its constituent granulin repeats repress transcription from cellular promoters.
abstract: Progranulin (also known as granulin/epithelin precursor, GEP) is composed of seven granulin/epithelin repeats (granulins) and functions both as a full-length protein and as individual granulins. It is a secretory protein but a substantial amount of GEP is found inside cells, some in complexes with positive transcription elongation factor b (P-TEFb). GEP and certain granulins interact with the cyclin T1 subunit of P-TEFb, and with its HIV-1 Tat co-factor, leading to repression of transcription from the HIV promoter. We show that GEP lacking the signal peptide (GEPspm) remains inside cells and, like wild-type GEP, interacts with cyclin T1 and Tat. GEPspm represses transcription from the HIV-1 promoter at the RNA level. Granulins that bind cyclin T1 are phosphorylated by P-TEFb in vivo and in vitro on serine residues. GEPspm and those granulins that interact with cyclin T1 also inhibit transcription from cellular cad and c-myc promoters, which are highly dependent on P-TEFb, but not from the PCNA promoter. In addition, GEPspm and granulins repress transcriptional activation by VP16 or c-Myc, proteins that bind and recruit P-TEFb to responsive promoters. These data suggest that intracellular GEP is a promoter-specific transcriptional repressor that modulates the function of cellular and viral transcription factors.
authors.affiliation: Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Mainul
authors.initials: M
authors.lastname: Hoque
authors.forename: Michael B
authors.initials: MB
authors.lastname: Mathews
authors.forename: Tsafi
authors.initials: T
authors.lastname: Pe'ery
mesh_terms: D000818:Animals; D001221:Aspartate Carbamoyltransferase / Q000235:genetics; D001665:Binding Sites; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000235:genetics; D056906:Cyclin T / Q000235:genetics; D004080:Dihydroorotase / Q000235:genetics; D015536:Down-Regulation; D016259:Genes, myc; D000077155:Granulins; D015497:HIV-1 / Q000235:genetics; D019073:HT29 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics; D000077153:Progranulins; D011401:Promoter Regions, Genetic; D021382:Protein Sorting Signals / Q000235:genetics; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: C033626:CAD trifunctional enzyme; C503684:CCNT1 protein, human; D056906:Cyclin T; C492314:GRN protein, human; C070633:Gal-VP16; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D000077153:Progranulins; D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D054322:tat Gene Products, Human Immunodeficiency Virus; D001221:Aspartate Carbamoyltransferase; D042925:Positive Transcriptional Elongation Factor B; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)