Activated polymorphonuclear leukocytes rapidly synthesize retinoic acid receptor-alpha: a mechanism for translational control of transcriptional events.
In addition to releasing preformed granular proteins, polymorphonuclear leukocytes (PMNs) synthesize chemokines and other factors under transcriptional control. Here we demonstrate that PMNs express an inducible transcriptional modulator by signal-dependent activation of specialized mechanisms that regulate messenger RNA (mRNA) translation. HL-60 myelocytic cells differentiated to surrogate PMNs respond to activation by platelet activating factor by initiating translation and with appearance of specific mRNA transcripts in polyribosomes. cDNA array analysis of the polyribosome fraction demonstrated that retinoic acid receptor (RAR)-alpha, a transcription factor that controls the expression of multiple genes, is one of the polyribosome-associated transcripts. Quiescent surrogate HL60 PMNs and primary human PMNs contain constitutive message for RAR-alpha but little or no protein. RAR-alpha protein is rapidly synthesized in response to platelet activating factor under the control of a specialized translational regulator, mammalian target of rapamycin, and is blocked by the therapeutic macrolide rapamycin, events consistent with features of the 5' untranslated region of the transcript. Newly synthesized RAR-alpha modulates production of interleukin-8. Rapid expression of a transcription factor under translational control is a previously unrecognized mechanism in human PMNs that indicates unexpected diversity in gene regulation in this critical innate immune effector cell.
Yost
Christian C
CC
Department of Pediatrics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
Denis
Melvin M
MM
Lindemann
Stephan
S
Rubner
Frederick J
FJ
Marathe
Gopal K
GK
Buerke
Michael
M
McIntyre
Thomas M
TM
Weyrich
Andrew S
AS
Zimmerman
Guy A
GA
D020121:5' Untranslated Regions; D002454:Cell Differentiation; D018076:DNA, Complementary / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D018922:HL-60 Cells; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008958:Models, Molecular; D009504:Neutrophils / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D017433:Protein Structure, Secondary; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis*; D000072482:Retinoic Acid Receptor alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic
D020121:5' Untranslated Regions; D018076:DNA, Complementary; D016209:Interleukin-8; C000607071:RARA protein, human; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha