The homeobox protein Prox1 is a negative modulator of ERR{alpha}/PGC-1{alpha} bioenergetic functions.
Estrogen-related receptor alpha (ERRalpha) and proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) play central roles in the transcriptional control of energy homeostasis, but little is known about factors regulating their activity. Here we identified the homeobox protein prospero-related homeobox 1 (Prox1) as one such factor. Prox1 interacts with ERRalpha and PGC-1alpha, occupies promoters of metabolic genes on a genome-wide scale, and inhibits the activity of the ERRalpha/PGC-1alpha complex. DNA motif analysis suggests that Prox1 interacts with the genome through tethering to ERRalpha and other factors. Importantly, ablation of Prox1 and ERRalpha have opposite effects on the respiratory capacity of liver cells, revealing an unexpected role for Prox1 in the control of energy homeostasis.
Charest-Marcotte
Alexis
A
Goodman Cancer Centre, McGill University, Montréal, Québec, Canada.
Dufour
Catherine R
CR
Wilson
Brian J
BJ
Tremblay
Annie M
AM
Eichner
Lillian J
LJ
Arlow
Daniel H
DH
Mootha
Vamsi K
VK
Giguère
Vincent
V
D000818:Animals; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D018085:Regulon / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor; D000098551:Prospero-Related Homeobox 1 Protein
D018398:Homeodomain Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000097983:ERRalpha Estrogen-Related Receptor; D000098551:Prospero-Related Homeobox 1 Protein; C485290:Ppargc1a protein, mouse