Translational Regulation of the JunD Messenger RNA

Abstract

JunD, a member of the Jun family of nuclear transcription proteins, dimerizes with Fos family members or other Jun proteins (c-Jun or JunB) to form the activator protein 1 (AP-1) transcription factor. The junD gene contains no introns and generates a single mRNA. Here we show that two predominant JunD isoforms are generated by alternative initiation of translation, a 39-kDa full-length JunD protein (JunD-FL) by initiation at the first AUG codon downstream of the mRNA 5′ cap and a shorter, 34-kDa JunD protein (ΔJunD) by initiation at a second in-frame AUG codon. The JunD mRNA contains a long, G/C-rich 5′-untranslated region that is predicted to be highly structured and is important for regulating the ratio of JunD-FL and ΔJunD protein expression. A third functional out-of-frame AUG directs translation from a short open reading frame positioned between the JunD-FL and ΔJunD start sites. In addition, three non-AUG codons also support translation, an ACG codon (in-frame with JunD) and a CUG are positioned in the 5′-untranslated region, and a CUG codon (also in-frame with JunD) is located downstream of the short open reading frame . Mutation of these start sites individually had no affect on ΔJunD protein levels, but mutation of multiple upstream start sites led to an increase in ΔJunD protein levels, indicating that these codons can function cumulatively to suppress ΔJunD translation. Finally, we show that the JunD mRNA does not possess an internal ribosome entry site and is translated in a cap-dependent manner. JunD, a member of the Jun family of nuclear transcription proteins, dimerizes with Fos family members or other Jun proteins (c-Jun or JunB) to form the activator protein 1 (AP-1) transcription factor. The junD gene contains no introns and generates a single mRNA. Here we show that two predominant JunD isoforms are generated by alternative initiation of translation, a 39-kDa full-length JunD protein (JunD-FL) by initiation at the first AUG codon downstream of the mRNA 5′ cap and a shorter, 34-kDa JunD protein (ΔJunD) by initiation at a second in-frame AUG codon. The JunD mRNA contains a long, G/C-rich 5′-untranslated region that is predicted to be highly structured and is important for regulating the ratio of JunD-FL and ΔJunD protein expression. A third functional out-of-frame AUG directs translation from a short open reading frame positioned between the JunD-FL and ΔJunD start sites. In addition, three non-AUG codons also support translation, an ACG codon (in-frame with JunD) and a CUG are positioned in the 5′-untranslated region, and a CUG codon (also in-frame with JunD) is located downstream of the short open reading frame . Mutation of these start sites individually had no affect on ΔJunD protein levels, but mutation of multiple upstream start sites led to an increase in ΔJunD protein levels, indicating that these codons can function cumulatively to suppress ΔJunD translation. Finally, we show that the JunD mRNA does not possess an internal ribosome entry site and is translated in a cap-dependent manner. open reading frame untranslated region cytomegalovirus myc-his-B phosphate-buffered saline containing 0.1% Tween 20 encephalomyocarditis virus internal ribosome entry site CCAAT/enhancer-binding protein eukaryotic initiation factor 4F Chinese hamster ovary wild type JunD is a basic region leucine zipper DNA-binding protein and a member of the Jun family of proteins, which also includes c-Jun and JunB (1Ryder K. Lanahan A. Perez-Albuerne E. Nathans D. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 1500-1503Crossref PubMed Scopus (367) Google Scholar, 2Berger I. Shaul Y. Oncogene. 1991; 6: 561-566PubMed Google Scholar). Jun proteins can homodimerize or heterodimerize with other Jun family members or heterodimerize with Fos family members (cFos, FosB, Fra-1, and Fra-2) to form the activator protein 1 transcription factor (3Nakabeppu Y. Ryder K. Nathans D. Cell. 1988; 55: 907-915Abstract Full Text PDF PubMed Scopus (531) Google Scholar, 4Halazonetis T.D. Georgopoulos K. Greenberg M.E. Leder P. Cell. 1988; 55: 917-924Abstract Full Text PDF PubMed Scopus (769) Google Scholar, 5Smeal T. Angel P. Meek J. Karin M. Genes Dev. 1989; 3: 2091-2100Crossref PubMed Scopus (185) Google Scholar). Activator protein 1 binds to the tetradecanoyl-13-phorbol acetate response element (TGA(G/C)TCA) located within the promoters of a wide range of genes, many important for regulation of cell growth and transformation (6Hirai S. Yaniv M. New Biol. 1989; 1: 181-191PubMed Google Scholar). Activator protein 1 is also an important signaling component in cell stress responses to UV irradiation, hypoxia, and cytokines (7Angel P. Karin M. Biochim. Biophys. Acta. 1991; 1072: 129-157Crossref PubMed Scopus (3279) Google Scholar, 8Wisdom R. Exp. Cell Res. 1999; 253: 180-185Crossref PubMed Scopus (339) Google Scholar, 9Shaulian E. Karin M. Oncogene. 2001; 20: 2390-2400Crossref PubMed Scopus (1394) Google Scholar). Several studies show that JunD has unique properties compared with c-Jun and JunB. Mice lacking c-Jun or JunB are not viable, whereas mice lacking JunD are viable with only mild growth defects and some abnormalities in spermatogenesis (10Hilberg F. Aguzzi A. Howells N. Wagner E.F. Nature. 1993; 365: 179-181Crossref PubMed Scopus (468) Google Scholar, 11Schorpp-Kistner M. Wang Z.Q. Angel P. Wagner E.F. EMBO J. 1999; 18: 934-948Crossref PubMed Scopus (218) Google Scholar, 12Thepot D. Weitzman J.B. Barra J. Segretain D. Stinnakre M.G. Babinet C. Yaniv M. Development. 2000; 127: 143-153PubMed Google Scholar). Overexpression of c-Jun or JunD exerts antagonistic effects on fibroblasts; c-Jun promotes cell proliferation and cooperates with activated ras to transform cells, whereas JunD overexpression slows cell growth and antagonizes transformation by ras (13Schutte J. Minna J.D. Birrer M.J. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 2257-2261Crossref PubMed Scopus (217) Google Scholar, 14Castellazzi M. Spyrou G., La Vista N. Dangy J.P. Piu F. Yaniv M. Brun G. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 8890-8894Crossref PubMed Scopus (126) Google Scholar, 15Pfarr C.M. Mechta F. Spyrou G. Lallemand D. Carillo S. Yaniv M. Cell. 1994; 76: 747-760Abstract Full Text PDF PubMed Scopus (287) Google Scholar). c-Jun and JunB behave as “early response genes” whose expression, at both the mRNA and protein levels, increases as cells enter the G1 phase of the cell cycle after serum stimulation (16Ryseck R.P. Hirai S.I. Yaniv M. Bravo R. Nature. 1988; 334: 535-537Crossref PubMed Scopus (385) Google Scholar, 17Ryder K. Nathans D. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 8464-8467Crossref PubMed Scopus (339) Google Scholar). JunD expression is less responsive to serum levels but is significantly increased as cells enter quiescence (1Ryder K. Lanahan A. Perez-Albuerne E. Nathans D. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 1500-1503Crossref PubMed Scopus (367) Google Scholar, 18Lallemand D. Spyrou G. Yaniv M. Pfarr C.M. Oncogene. 1997; 14: 819-830Crossref PubMed Scopus (132) Google Scholar). Similar to the other Jun family members, the junD gene has no introns and produces a single messenger RNA (19Sullivan M. Olsen A.S. Houslay M.D. Cell Signal. 1999; 11: 735-742Crossref PubMed Scopus (19) Google Scholar). The JunD mRNA encodes two ubiquitously expressed protein isoforms, JunD-FL and ΔJunD, generated by translational initiation at two AUG codons that are in-frame with one another (20Okazaki S. Ito T., Ui, M. Watanabe T. Yoshimatsu K. Iba H. Biochem. Biophys. Res. Commun. 1998; 250: 347-353Crossref PubMed Scopus (22) Google Scholar). A small out-of-frame AUG-initiated open reading frame (μORF)1is positioned between these two AUG codons. We show that in addition to these three AUG codons, three non-AUG start codons are functional for initiation of translation, a CUG and an ACG, located within the 5′-untranslated region (5′-UTR), and a CUG that resides between the JunD-FL and ΔJunD start sites. Thus, a total of six translation start sites reside within the rodent JunD mRNA. The JunD mRNA also contains a long, G/C-rich that is predicted to a of and to be highly structured (1Ryder K. Lanahan A. Perez-Albuerne E. Nathans D. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 1500-1503Crossref PubMed Scopus (367) Google Scholar, 2Berger I. Shaul Y. Oncogene. 1991; 6: 561-566PubMed Google Scholar, A. J. J. J. Oncogene. 2000; PubMed Scopus Google Scholar). studies that long, can be to cap-dependent translation M. J. Biol. 1991; Full Text PDF PubMed Google Scholar, J. Biochem. PubMed Scopus Google Scholar). In we the of the JunD and the of functional initiation start codons in translation of the JunD-FL and ΔJunD that the JunD is important in regulating the ratio of JunD-FL and we show that the JunD mRNA is translated in a cap-dependent and that upstream codons cumulatively to expression of the ΔJunD A cell cell cell cell and and cell and in with serum and cells in with serum and protein or RNA cells at a of or cells at a of or of total or the to the for protein or after cells in and the to the with a The full-length JunD as the a of the JunD to as the and a of the JunD to the The JunD by the for full-length JunD The JunD open reading frame by as the The as the for of the JunD the expression after with and JunD or JunD containing the 5′-untranslated region by as A site generated upstream of the region the to the The JunD from the region the of the by and as and The from the region to the of the by and as and the after with of JunD the and by The of can be generated as site generated in the expression downstream of the open reading The and to the 5′ region of JunD that the The expression after with and and to an containing the JunD 5′ region, and from the The the after with The containing the encephalomyocarditis virus a from and K. J. 2000; PubMed Scopus Google Scholar). A the by first site within the region upstream of the a containing a at for and on for 20 A. J. J. J. Oncogene. 2000; PubMed Scopus Google Scholar). The at for 1 and and the cell 1 1 1 from as D. Spyrou G. Yaniv M. Pfarr C.M. Oncogene. 1997; 14: 819-830Crossref PubMed Scopus (132) Google Scholar). a from the of C. protein the protein of protein in at by on and to for 1 at phosphate-buffered saline containing 0.1% Tween 20 with in with serum and at for 1 with an in with serum and for 1 at with The a JunD proteins a or a C.M. Mechta F. Spyrou G. Lallemand D. Carillo S. Yaniv M. Cell. 1994; 76: 747-760Abstract Full Text PDF PubMed Scopus (287) Google Scholar). RNA RNA by on containing and to with of in containing Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). with and 0.1% at and to a for a A to the region generated as The region of by as the and as the The and with the to the JunD protein levels, cell generated from and a of cell with a for a of JunD and cell with a of JunD C.M. Mechta F. Spyrou G. Lallemand D. Carillo S. Yaniv M. Cell. 1994; 76: 747-760Abstract Full Text PDF PubMed Scopus (287) Google Scholar). of these are highly with no to the other Jun proteins, and both not of the two isoforms of The full-length JunD at and a ΔJunD, at (20Okazaki S. Ito T., Ui, M. Watanabe T. Yoshimatsu K. Iba H. Biochem. Biophys. Res. Commun. 1998; 250: 347-353Crossref PubMed Scopus (22) Google Scholar). expressed JunD-FL and ΔJunD at the ratio of JunD-FL to ΔJunD between cell and cells expressed JunD-FL and ΔJunD at a whereas and cells expressed JunD-FL at levels ΔJunD of the JunD mRNA three AUG initiation codons positioned within to support translational three start codons are between and The first AUG in the JunD mRNA downstream of the 5′ cap to JunD-FL (1Ryder K. Lanahan A. Perez-Albuerne E. Nathans D. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 1500-1503Crossref PubMed Scopus (367) Google Scholar). The third AUG downstream of the 5′ cap is in-frame with and the predicted protein generated from the start site is with the ΔJunD in The second AUG downstream of the 5′ cap is out-of-frame with the to as the a AUG codons are in the and JunD of three open reading with AUG within JunD The of the protein or for is in the at The and JunD-FL and ΔJunD, of the of the AUG start codons within JunD mRNA with an are with a at and at the codon can translation of the ΔJunD JunD and The an in-frame with the of JunD, of JunD proteins by The of the three AUG codons in the and codons, and only the codon The and cells, and expression by with a for the The both JunD-FL and ΔJunD The and not but both generated the ΔJunD the of the AUG in ΔJunD expression, codon to the and of the to to the of translational initiation from the start codon M. Cell. Full Text PDF PubMed Scopus Google Scholar). The AUG of ΔJunD, and the mutation ΔJunD protein expression and these that JunD-FL translation is at the AUG and ΔJunD translation is at the codon. the translation of ΔJunD, the AUG to an ACG codon to translational the codon to a codon to of that had translated the and cells, and cell by the start codon codon significantly the expression of ΔJunD or JunD-FL the AUG and that to in to A single the the in-frame with ΔJunD and the AUG out-of-frame with mutation translation at the codon to and a protein in-frame with the that predicted to be the to a that also the AUG mutation to and generated a protein and ΔJunD but not JunD-FL and the is by an Mutation of the start codon led to of the protein and indicating that the is initiation at the AUG codon. the mutation the mutation significantly the ΔJunD protein compared with that the the predicted JunD also a The protein generated by within the rodent and also by JunD with the the by mutation of the start codon and The of the JunD mRNA is a and in rodent and G/C-rich that is predicted to a of A. J. J. J. Oncogene. 2000; PubMed Scopus Google Scholar). the and from the mRNA 5′ cap to the AUG codon J. M. J. Biol. 1999; PubMed Scopus Google Scholar, M. J. RNA and Scholar). The and had of The predicted of for the and both possess three with the first positioned only from the JunD mRNA 5′ cap the of the in JunD mRNA translation, generated that the or the JunD containing the JunD and that a 5′-untranslated region from the RNA and by with a for the region of the mRNA. levels of mRNA expressed by the and that JunD-FL protein levels in cells with the JunD by a in the ratio of JunD-FL to ΔJunD The expression ratio of from a ratio to that for the JunD isoforms that the JunD has a in the ratio of JunD-FL and ΔJunD in cells and that the are a with which to JunD of the JunD the protein of containing the JunD 5′-untranslated region of the and JunD or which possess a 5′-untranslated region from the or in A cells, and cell for expression of JunD isoforms by RNA by with a The to the codon translation initiation in the of the JunD to in the and expression from these in A from the mutation that the AUG in-frame with the (ΔJunD) Similar to the the by mutation of the start codon Mutation of the AUG codon or the codon in the had no affect on JunD-FL or ΔJunD protein levels not The containing a mutation also generated an that at a JunD-FL are no other AUG codons upstream of the AUG codon. the of the the JunD mRNA upstream of the AUG for non-AUG start codons. A alternative initiation CUG within the JunD that in-frame with the Mutation of codon the indicating that CUG translation initiation within the JunD from the in cells generated the JunD-FL and ΔJunD but two in highly cells, a JunD-FL and a between JunD-FL and ΔJunD The JunD mRNA for alternative initiation codons that in-frame with JunD-FL and ACG within the JunD downstream of the start site and a CUG codon downstream of the codon at that these in-frame JunD that these two alternative start sites. Mutation of the start codon expression of the and mutation of the codon expression of the protein alternative start a CUG located from the mRNA 5′ also but had no affect on the expression of the not these that the JunD mRNA has multiple sites of translation initiation that at both AUG and non-AUG start codons. of the start codons within the to a codon Mutation of the codon led to increased protein levels, and the mutation led to increased protein the single mutation of upstream start start had no affect on ΔJunD protein levels not The mutation of upstream start codons in to increased ΔJunD protein expression. and led to a increase in ΔJunD protein levels and A the and codons led to a increase in ΔJunD protein levels, and a mutation of the and codons led to a increase in ΔJunD protein levels Mutation of upstream start sites led to the increase in ΔJunD protein expression no in JunD mRNA expression between the as by not the 5′ region of the JunD mRNA an internal ribosome entry site as A of the JunD mRNA from the 5′ cap to the start site within the of a containing and a the encephalomyocarditis virus M.J. E. J. 1988; PubMed Google Scholar). expression of the by cap-dependent translation of the mRNA. the only translated by that the upstream or to the by an or cells, and and in cell The led to a increase in the ratio of to in cell compared with the containing no with the JunD led to an increase in the ratio of to of on the cell cap-dependent translation, a upstream of in the to translation of the cap-dependent but had no or increased expression of the an A. J. J. J. Oncogene. 2000; PubMed Scopus Google Scholar). with or a The containing the an increased ratio of to compared with the with no The JunD with a in to the an an for JunD the JunD from the 5′ cap the region downstream of a to the but translation of the JunD an JunD expression not expressed at levels not these that the JunD mRNA does not possess an but is translated in a cap-dependent manner. In we the that within the JunD mRNA in regulating expression of the two JunD protein isoforms, JunD-FL and We that the JunD the ratio of JunD-FL and ΔJunD and that a small that resides between the JunD-FL and ΔJunD start out-of-frame with JunD, is translated by We also that the JunD mRNA contains three non-AUG codons that can translation, not as as the JunD AUG codons. of these non-AUG codons, a CUG upstream of JunD-FL and a CUG downstream of the that are in-frame with JunD-FL and are isoforms of JunD that can be The other non-AUG an ACG codon upstream of the JunD-FL start is in-frame with the Mutation of upstream start codons led to increased expression from the downstream codon but significantly the expression of mutation of upstream start sites in led to a increase in ΔJunD expression. to the of translation, the eukaryotic initiation factor 4F of and binds to the cap of mRNA and the of the and eukaryotic initiation The the in a 5′ to the first AUG by a translation M. J. Biol. 1991; Full Text PDF PubMed Google Scholar, N. of Scholar). The important for translational initiation are an A in the or a in the the A of the start codon is M. Cell. Full Text PDF PubMed Scopus Google Scholar). A small of has to protein from one start but is to the of start codons to and initiation codons the for and to multiple isoforms by of translation start sites by C. A. Genes Dev. 2000; 14: PubMed Google Scholar). some as basic growth and non-AUG codons for translational a that also to translation of multiple protein isoforms A. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: PubMed Scopus Google Scholar, Cell. 1988; Full Text PDF PubMed Scopus Google Scholar). We that the JunD-FL and ΔJunD isoforms are generated by alternative translational initiation at AUG codons within the JunD mRNA The JunD AUG is by a with a at and a at the AUG codon of JunD and the ΔJunD start site in the or of the JunD The JunD JunD-FL expression and the ratio of JunD-FL to ΔJunD The JunD the other Jun family is and The JunD has the of Jun mRNA for the and for and is a on with a predicted of of and for and Y. S. Res. 2000; PubMed Scopus Google Scholar). In and in that are to translation. with of less translation by the ribosome at the 5′ of the mRNA and to downstream AUG codons M. Cell. Biol. 1989; PubMed Scopus Google Scholar, M. J. 1999; PubMed Scopus Google Scholar). In addition, the highly structured of protein and the to translational initiation by J. Biol. Full Text PDF PubMed Google Scholar, M.G. Biochem. Biophys. Res. Commun. 2001; PubMed Scopus Google Scholar, J. Biol. 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Oncogene. 2000; PubMed Scopus Google Scholar). of a the JunD not the ratio of the the of the a by of the the from the we one to the JunD mRNA for The mRNA contains two upstream of the initiation codon that to to S. N. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The JunD mRNA has a located upstream of the ΔJunD start Mutation of JunD to had no on ΔJunD protein levels not these that the JunD mRNA does not an and that the mRNA is translated in a cap-dependent manner. the or the be to increased of the AUG in the of the JunD In the the to the JunD mRNA but an increased of to the in JunD-FL expression ΔJunD In the ribosome from the downstream of the to initiation at the The two as to the JunD mRNA are not and in that to multiple translation initiation sites. are with both in the regulation of JunD mRNA translation. We a total of six translation initiation that can within the JunD mRNA at AUG and non-AUG codons. translation initiation sites for the as AUG codons. a at is important for with M. EMBO J. 1997; PubMed Scopus Google Scholar). of the functional non-AUG codons that are in that a at and an A in the R. D. EMBO J. 1994; PubMed Scopus Google Scholar). of the three alternative start codons in the JunD mRNA also contains a at and a at that of these codons is in a for and A CUG start codon in the can support translation and a that be in-frame with the ACG positioned downstream of the codon is also functional for initiation and a of Finally, within the is a functional CUG codon that is also in-frame with from a JunD protein the first lacking in these that are JunD isoforms and two generated from the JunD mRNA. we the expression of these JunD isoforms from expression only the two protein isoforms of JunD in and cell (20Okazaki S. Ito T., Ui, M. Watanabe T. Yoshimatsu K. Iba H. Biochem. Biophys. Res. Commun. 1998; 250: 347-353Crossref PubMed Scopus (22) Google Scholar). with the predicted and of JunD-FL no expression of the or protein be to levels is not of regulation has for a growth factor that is translated initiation at a CUG codon and is in cells but is in S. C. S. F. F. H. J. Cell Biol. PubMed Scopus Google Scholar). to affect translation of downstream Cell. Biol. 2000; 20: PubMed Scopus Google Scholar). expression of and are by an upstream in a on and Y. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). Mutation of JunD mRNA upstream start codons, the and AUG codons that for translation, not significantly affect ΔJunD protein start codon to increased expression from the downstream start but increase not to the protein levels from the upstream start codon mutation of the start codon not the protein levels to increase to the of the translation at and in the mRNA not In addition, the two JunD isoforms expressed at from the or JunD and we not that ratio to that a of at initiation codons a and that upstream start codons individually not affect ΔJunD expression. mutation of multiple upstream start codons led to a increase in initiation from ΔJunD, that these codons can ΔJunD expression in a that from of that the upstream codons, both AUG and are important for regulating ΔJunD protein levels within the studies that JunD-FL and ΔJunD are with other nuclear the protein binds to JunD-FL the first and JunD-FL C. S. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, Pfarr C.M. Res. 2001; Google Scholar). ΔJunD does not and is by In addition, the and JunD-FL ΔJunD both JunD isoforms a and three sites. the of of the JunD mRNA regulating expression of both JunD isoforms, functional between the JunD-FL and ΔJunD proteins to Finally, in addition to JunD-FL and ΔJunD, we two JunD isoforms expressed at levels, the functional of JunD and activator protein 1 We are to C. for N. for expression and cell and K. for We also and M. C. S. C. D. M. and for and reading of the