Target gene specificity of USF-1 is directed via p38-mediated phosphorylation-dependent acetylation.
How transcription factors interpret the output from signal transduction pathways to drive distinct programs of gene expression is a key issue that underpins development and disease. The ubiquitously expressed basic-helix-loop-helix leucine zipper upstream stimulating factor-1 binds E-box regulatory elements (CANNTG) to regulate a wide number of gene networks. In particular, USF-1 is a key component of the tanning process. Following UV irradiation, USF-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the POMC, MC1R, TYR, TYRP-1 and DCT genes. However, how phosphorylation on Thr-153 might affect the activity of USF-1 is unclear. Here we show that, in response to DNA damage, oxidative stress and cellular infection USF-1 is acetylated in a phospho-Thr-153-dependent fashion. Phospho-acetylated USF-1 is nuclear and interacts with DNA but displays altered gene regulatory properties. Phospho-acetylated USF-1 is thus proposed to be associated with loss of transcriptional activation properties toward several target genes implicated in pigmentation process and cell cycle regulation. The identification of this critical stress-dependent USF-1 modification gives new insights into understanding USF-1 gene expression modulation associated with cancer development.
Corre
Sébastien
S
Signaling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted RH8 OTL, United Kingdom.
Primot
Aline
A
Baron
Yorann
Y
Le Seyec
Jacques
J
Goding
Colin
C
Galibert
Marie-Dominique
MD
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D004249:DNA Damage; D005786:Gene Expression Regulation; D006801:Humans; D008546:Melanoma, Experimental; D051379:Mice; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D013912:Threonine / Q000737:chemistry; D051720:Upstream Stimulatory Factors / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors; D013912:Threonine; D048051:p38 Mitogen-Activated Protein Kinases