Involvement of retinoic acid receptor-alpha-mediated signaling pathway in induction of CD38 cell-surface antigen.
Human leukocyte antigen CD38, a 45-kD single-chain, transmembrane glycoprotein, is a bifunctional ectoenzyme that participates in signal transduction pathways involved in the regulation of cell growth and differentiation. In this study, we demonstrate the nature of retinoid receptors involved in retinoic acid-induced expression of CD38 protein in the human myeloblastic leukemia cell line HL-60. We used a variant HL-60 cell line, HL-60R, in which retinoid receptor function has been abrogated by a trans-dominant negative mutation. We introduced the normal retinoic acid receptors (RAR)-alpha, -beta, and -gamma or retinoid X receptor (RXR)-alpha into HL-60R cells by retroviral vector-mediated gene transfer. Based on experiments using these cell lines and receptor-specific synthetic retinoids that preferentially bind to one of the RARs or RXRs, we conclude that RAR-alpha is involved in retinoid-induced CD38 expression in HL-60 cells. Further evidence included our demonstration that blocking of RAR-alpha with the antagonist Ro 41-5253 completely suppressed the retinoid-induced expression of CD38 mRNA transcript and the production of CD38 protein in HL-60 cells. Various tissues from transgenic mice that expressed an antisense construct of RAR-alpha lacked or produced very low levels of CD38. As expected, the tissues from transgenic mice contained 50% to 80% reduced levels of RAR-alpha. These results suggest that regulation of CD38 expression, both in vitro and in vivo, is under the direct control of RAR-alpha retinoid receptors.
Mehta
K
K
Department of Bioimmunotherapy, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
McQueen
T
T
Manshouri
T
T
Andreeff
M
M
Collins
S
S
Albitar
M
M
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000235:genetics; D001565:Benzoates / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D016373:DNA, Antisense / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D008223:Lymphoma / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009699:N-Glycosyl Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D000097768:Retinoic Acid Receptor gamma
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD; D000943:Antigens, Differentiation; D001565:Benzoates; D002839:Chromans; D016373:DNA, Antisense; D018076:DNA, Complementary; D008562:Membrane Glycoproteins; D009699:N-Glycosyl Hydrolases; D009363:Neoplasm Proteins; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000607071:RARA protein, human; C000607072:Rara protein, mouse; C082925:retinoic acid receptor beta; C084904:Ro 41-5253; C498154:CD38 protein, human; C498155:Cd38 protein, mouse