Post-transcriptional regulation of MyD118 and GADD45 in human lung carcinoma cells during 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2- naphthalene carboxylic acid-induced apoptosis.
Recently, the novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) has been shown to inhibit cell growth and induce apoptosis in several human carcinoma cell lines. To understand the mechanism of AHPN action, we identified, using the differential display method, several genes that are differentially regulated by AHPN. The sequence of one of these genes was highly homologous to mouse MyD118, a gene closely related to GADD45. Both of these genes have been reported to play a role in negative growth control and apoptosis. hMyD118 was expressed in a variety of tissues, including liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, and peripheral blood leukocytes. The levels of both hMyD118 and GADD45 mRNA was rapidly increased in a number of carcinoma cell lines after treatment with AHPN. This increase was specific for AHPN because retinoic acid, a retinoic acid receptor-selective retinoid, and an retinoid X receptor-selective retinoid were ineffective. These results suggest that this action of AHPN involves a novel mechanism that is independent of the nuclear retinoid receptors. AHPN increases the half-life of hMyD118 and GADD45 mRNA by >9-fold, indicating that it causes an increase in the stability of these mRNAs. The caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoro-methylketone (ZVAD. fmk) had no effect on the induction of hMyD118, indicating that this increase occurred independently of caspase activation. Our study demonstrates that the inhibition of cell growth by AHPN is accompanied by an increase in hMyD118 and GADD45 mRNA, and that this enhancement is regulated at a post-transcriptional level. Our results support a role for MyD118 and GADD45 in the negative growth control by AHPN.
Sakaue
M
M
Cell Biology Section, Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Adachi
H
H
Jetten
A M
AM
D000595:Amino Acid Sequence; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001483:Base Sequence; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D012176:Retinoids / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D020169:Caspases; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D012176:Retinoids; D000097642:GADD45 Proteins; C099555:CD 437; C086470:GADD45B protein, human; C490125:Gadd45b protein, mouse