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. J. Cell. Physiol. 223: 224–233, 2010.