Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\28553927
.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Elife
2017 ; 6
(ä): ä Nephropedia Template TP
Chung J
; Wittig JG
; Ghamari A
; Maeda M
; Dailey TA
; Bergonia H
; Kafina MD
; Coughlin EE
; Minogue CE
; Hebert AS
; Li L
; Kaplan J
; Lodish HF
; Bauer DE
; Orkin SH
; Cantor AB
; Maeda T
; Phillips JD
; Coon JJ
; Pagliarini DJ
; Dailey HA
; Paw BH
Elife
2017[May]; 6
(ä): ä PMID28553927
show ga
Heme is required for survival of all cells, and in most eukaryotes, is produced
through a series of eight enzymatic reactions. Although heme production is
critical for many cellular processes, how it is coupled to cellular
differentiation is unknown. Here, using zebrafish, murine, and human models, we
show that erythropoietin (EPO) signaling, together with the GATA1 transcriptional
target, AKAP10, regulates heme biosynthesis during erythropoiesis at the outer
mitochondrial membrane. This integrated pathway culminates with the direct
phosphorylation of the crucial heme biosynthetic enzyme, ferrochelatase (FECH) by
protein kinase A (PKA). Biochemical, pharmacological, and genetic inhibition of
this signaling pathway result in a block in hemoglobin production and concomitant
intracellular accumulation of protoporphyrin intermediates. Broadly, our results
implicate aberrant PKA signaling in the pathogenesis of hematologic diseases. We
propose a unifying model in which the erythroid transcriptional program works in
concert with post-translational mechanisms to regulate heme metabolism during
normal development.
|*Signal Transduction
[MESH]
|A Kinase Anchor Proteins/*metabolism
[MESH]
|Animals
[MESH]
|Cyclic AMP-Dependent Protein Kinases/metabolism
[MESH]
free
free
free
