Evidence for the Involvement of Retinoic Acid Receptor RARα-dependent Signaling Pathway in the Induction of Tissue Transglutaminase and Apoptosis by Retinoids

In this study, we show that all-trans-retinoic acid (RA) is a potent inducer of tissue transglutaminase (TGase II) and apoptosis in the rat tracheobronchial epithelial cell line SPOC-1. We demonstrate that these cells express the retinoid receptors RARα, RARγ, and RXRβ. To identify which of these receptors are involved in regulating these processes, we analyzed the effects of several receptor-selective agonists, an antagonist, and a dominant-negative RARα. We show that the RAR-selective retinoid SRI-6751-84 strongly increased TGase II expression at both the protein and mRNA levels, whereas the RXR-selective retinoid SR11217 had little effect. The RARα-selective retinoid Ro40-6055 was also able to induce TGase II, whereas the RARγ-selective retinoid CD437 was inactive. The induction of TGase II by the RAR-selective retinoid was completely inhibited by the RARα-antagonist Ro41-5253. Overexpression of a truncated RARα gene with dominant-negative activity also inhibited the induction of TGase II expression. The increase in TGase II is associated with an induction of apoptosis as revealed by DNA fragmentation and the generation of apoptotic cells. We demonstrate that apoptosis is affected by retinoids in a manner similar to TGase II. Our results suggest that the induction of TGase II expression and apoptosis in SPOC-1 cells are mediated through an RARα-dependent signaling pathway. In this study, we show that all-trans-retinoic acid (RA) is a potent inducer of tissue transglutaminase (TGase II) and apoptosis in the rat tracheobronchial epithelial cell line SPOC-1. We demonstrate that these cells express the retinoid receptors RARα, RARγ, and RXRβ. To identify which of these receptors are involved in regulating these processes, we analyzed the effects of several receptor-selective agonists, an antagonist, and a dominant-negative RARα. We show that the RAR-selective retinoid SRI-6751-84 strongly increased TGase II expression at both the protein and mRNA levels, whereas the RXR-selective retinoid SR11217 had little effect. The RARα-selective retinoid Ro40-6055 was also able to induce TGase II, whereas the RARγ-selective retinoid CD437 was inactive. The induction of TGase II by the RAR-selective retinoid was completely inhibited by the RARα-antagonist Ro41-5253. Overexpression of a truncated RARα gene with dominant-negative activity also inhibited the induction of TGase II expression. The increase in TGase II is associated with an induction of apoptosis as revealed by DNA fragmentation and the generation of apoptotic cells. We demonstrate that apoptosis is affected by retinoids in a manner similar to TGase II. Our results suggest that the induction of TGase II expression and apoptosis in SPOC-1 cells are mediated through an RARα-dependent signaling pathway. INTRODUCTIONTransglutaminases (EC 2.3.2.13, TGases) ( 1The abbreviations used are: TGasetransglutaminaseLUCluciferaseCATchloramphenicol acetyltransferaseRAall-trans-retinoic acidRARretinoic acid receptorRXRretinoid X receptorRARERAR response elementRXRERXR response elementTGFtransforming growth factor. )are Ca2+-dependent enzymes catalyzing the formation of ε(γ-glutamyl)lysine cross-links between polypeptide chains(1Folk J.E. Annu. Rev. Biochem. 1980; 49: 517-531Crossref PubMed Scopus (869) Google Scholar). Several members of this gene family have been identified including the type I (epidermal) TGase (2Floyd E.E. Jetten A.M. Mol. Cell. Biol. 1989; 9: 4846-4851Crossref PubMed Scopus (103) Google Scholar, 3Phillips M.A. Stewart B.E. Qin Q. Chakravarty R. Floyd E.E. Jetten A.M. Rice R.H. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 9333-9337Crossref PubMed Scopus (102) Google Scholar) and type II (tissue) TGase(4Chiocca E.A. Davies P.J. Stein J.P. J. Biol. Chem. 1988; 263: 11584-11589Abstract Full Text PDF PubMed Google Scholar, 5Ikura K. Nasu T. Yokota H. Tsuchiya Y. Sasaki R. Chiba H. Biochemistry. 1988; 27: 2898-2905Crossref PubMed Scopus (149) Google Scholar). TGase I is induced during squamous differentiation and plays a role in the formation of the cross-linked envelope(2Floyd E.E. Jetten A.M. Mol. Cell. Biol. 1989; 9: 4846-4851Crossref PubMed Scopus (103) Google Scholar, 6Marvin K.W. George M.D. Fujimoto W. Saunders N.A. Bernacki S. Jetten A.M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 11026-11030Crossref PubMed Scopus (146) Google Scholar). The function of TGase II is less well established. TGase II has been implicated in the activation of several cytokines (7Eitan S. Schwartz M. Science. 1993; 261: 106-108Crossref PubMed Scopus (126) Google Scholar, 8Kojima S. Nara K. Rifkin D.B. J. Cell Biol. 1993; 121: 439-448Crossref PubMed Scopus (277) Google Scholar) and in signal transduction(9Nakaoka H. Perez D.M. Baek K.J. Das T. Husain A. Misono K. Im M.J. Graham R.M. Science. 1994; 264: 1593-1596Crossref PubMed Scopus (528) Google Scholar). Expression of TGase II has been found in association with apoptosis in several cell types, and a role for TGase II in this process has been suggested(10Fesus L. Thomazy V. Falus A. FEBS Lett. 1987; 224: 104-108Crossref PubMed Scopus (406) Google Scholar, 11Tarcsa E. Kedei N. Thomazy V. Fesus L. J. Biol. Chem. 1992; 267: 25648-25651Abstract Full Text PDF PubMed Google Scholar, 12Tomei L.D. Cope The of in Scholar). is a process of cell and is in the of cells during in as well as in L.D. Cope The of in Scholar, Rev. 1980; PubMed Scopus Google Scholar). the function of TGase II in apoptosis has to has been that TGase II the of M. M. J. Cell Biol. 1993; Google has been to induce TGase II expression in a of cell E.A. Davies P.J. Stein J.P. J. Biol. Chem. 1988; 263: 11584-11589Abstract Full Text PDF PubMed Google Scholar, T. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, M.D. Floyd E. Stein J.P. Jetten A.M. J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar, Rice R.H. Google Scholar, Biochem. PubMed Scopus Google Scholar, M. Fesus L. FEBS Lett. 1993; PubMed Scopus Google Scholar, George M.D. Jetten A.M. J. Cell Mol. Biol. 1992; PubMed Scopus Google Scholar, Stein J.P. E.A. J.P. V. Thomazy V. Fesus L. in and Scholar). In the of TGase II expression by at the E.A. Davies P.J. Stein J.P. J. Biol. Chem. 1988; 263: 11584-11589Abstract Full Text PDF PubMed Google Scholar). is that of the effects of gene expression are mediated by the activation of retinoid The and Scholar). The and gene family and The and Scholar). are in a and cell The and and the expression of this study, we the retinoid signaling that are involved in the induction of TGase II and apoptosis in rat tracheobronchial epithelial SPOC-1 cells several retinoid receptor-selective and an We have also this through the expression of a truncated RARα that as a dominant-negative S. S. R. K. R. 1992; PubMed Scopus Google Scholar). Our results that the induction of TGase II gene expression and apoptosis by is mediated through a retinoid signaling that rat epithelial cell line SPOC-1 was SPOC-1 and cells as George M.D. Jetten A.M. J. Cell Mol. Biol. 1992; PubMed Scopus Google Scholar, J. S. J. Cell Mol. Biol. Google Scholar). to and with was The RAR-selective retinoid SRI-6751-84 and the RXR-selective retinoid SR11217 and as M. M. Google Scholar, L. A. L. M. Science. 1992; PubMed Scopus Google Scholar). The RARγ-selective U. 1992; PubMed Scopus Google was by S. The RARα-selective retinoid Ro40-6055 and the RARα-antagonist M. L. M. W. M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: PubMed Scopus Google Scholar). in The of in the was analyzed by as M.D. Floyd E. Stein J.P. Jetten A.M. J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar). was by a the The TGase II P.J. E. PubMed Scopus Google Scholar) and TGase I Rice R.H. Cell. Full Text PDF PubMed Scopus Google Scholar) by J. and S. of and and as 1992; Google Scholar). The TGase II E.A. Davies P.J. Stein J.P. J. Biol. Chem. 1988; 263: 11584-11589Abstract Full Text PDF PubMed Google Scholar) was a Davies of for RARα, and and M. A. 1987; PubMed Scopus Google Scholar, N. M. A. H. A. A. 1988; PubMed Scopus Google Scholar, M. R. H. Saunders M. T. A. S. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar) whereas and U. A. R.M. 1992; PubMed Scopus Google Scholar) by and R. of the gene Schwartz Biochemistry. PubMed Scopus Google Scholar) was used as a for at with at for The was with at for was with at of SPOC-1 with S. M. H. J. N. H. V. 1994; PubMed Scopus Google Scholar) and K. U. R.M. Cell. Full Text PDF PubMed Scopus Google Scholar) V. and of SPOC-1 cells in tissue and the was to of growth The cells with of with of and of a expression the of M. R. H. Saunders M. T. A. S. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar) of DNA was to the cells in growth and with retinoids for activity was the activity was as by Mol. Cell. Biol. Scopus Google Scholar). at and in of SPOC-1 with in which a truncated RARα gene is the has been S. S. R. K. R. 1992; PubMed Scopus Google Scholar). SPOC-1 cells at the of The cells with the in the of as S. S. R. K. R. 1992; PubMed Scopus Google Scholar). a the was and cells for was and the cells was as J. 1994; Google Scholar). DNA was in a in and and by and in as J. 1994; Google Scholar). with and and in a of TGase I and II by epithelial SPOC-1 cells squamous cell differentiation and to express several squamous including TGase I and A.M. Fujimoto W. K.W. S. K.J. Bernacki Saunders N.A. M.A. to Scholar). of these with strongly the induction of TGase I as revealed by the TGase In of an increase in the of TGase II protein of TGase I expression at as as whereas TGase II was increased at The of TGase II was in SPOC-1 cells with as to cells. in an increase in TGase II a of and a of with The induction of TGase II by in and of and in SPOC-1 induction of TGase II by mediated by retinoid To which retinoid receptors involved in this the expression of and receptors in SPOC-1 cells was and SPOC-1 cells to SPOC-1 cells RARα, RARγ, and whereas and and of SPOC-1 cells for with the retinoid SRI-6751-84 increased the of and by and SRI-6751-84 also induced expression at induce as for TGase II was able to induce In to and epithelial George M.D. A. Jetten A.M. Cell PubMed Scopus Google induce mRNA in SPOC-1 cells of and in SPOC-1 cells. for with the RAR-selective retinoid SRI-6751-84 was to a and to for RARα, and and and of and by which the induction of TGase II, we the activity of several retinoids that to and To the of these retinoids in SPOC-1 cells with DNA a the of an The of the gene was with retinoid The RAR-selective retinoid which to and M. M. Google was able to induce of at through The RARα-selective retinoid Ro40-6055 and the RARγ-selective retinoid CD437 a increase in the of The RXR-selective retinoid SR11217 which to receptors and the formation of L. A. L. M. Science. 1992; PubMed Scopus Google a increase in gene activity at activation of by SR11217 is with the of for this response J. J. T. M. 1992; PubMed Scopus Google Scholar). In this RXR-selective retinoid strongly increased activity by whereas a induction was with and SRI-6751-84 at the of and by and and RXR-selective SRI-6751-84 and SPOC-1 cells with and with retinoids at the of activity was as was in to for in of TGase II by we analyzed the effects of these retinoids TGase II expression. of SPOC-1 cells for with these retinoids at and TGase II was by in the RAR-selective retinoid TGase II at SRI-6751-84 was potent in with in In the RXR-selective retinoid increase in the of TGase II protein suggest that activation of is for the induction of TGase II. The RARα-selective retinoid Ro40-6055 was as in TGase II expression as whereas the RARγ-selective retinoid was to induce TGase II results suggest an role for RARα in the of TGase II of TGase II protein by retinoid receptor-selective in SPOC-1 cells. with SRI-6751-84 Ro40-6055 CD437 at the for cells and analyzed for the of TGase II protein by increase in TGase II protein by retinoids was to increased of the revealed that with the RAR-selective retinoid SRI-6751-84 increased the of TGase II mRNA in a manner The for this was which is similar to that for the of SRI-6751-84 TGase II protein in with of SPOC-1 cells with the RXR-selective retinoid SR11217 to TGase II mRNA results are with the the in with induction of TGase II mRNA expression by receptor-selective retinoids in SPOC-1 cells. cells with the RAR-selective retinoid SRI-6751-84 and the RXR-selective retinoid at the of was and to a The was with for TGase II and the RXR-selective retinoid the induction of TGase II by the RAR-selective with a of SRI-6751-84 in the of of the RXR-selective retinoid SR11217 for and analyzed for TGase II revealed that the RXR-selective retinoid had the induction of TGase II expression by the RAR-selective retinoid of an RARα TGase II the signaling involved in the induction of TGase II by the of the RARα was We the of the of in the was able to the by the RAR-selective retinoid SRI-6751-84 in SPOC-1 cells. We the of the the induction of TGase II. with a of SRI-6751-84 and of the RARα of the cells and analyzed for TGase II expression. in of inhibited the induction of TGase II by was able to completely the induction of TGase II by has a for RARα which for the to TGase II of SPOC-1 cells with the had the of TGase of the RARα-selective the of and the of TGase II. SPOC-1 cells with with a of the RAR-selective retinoid SRI-6751-84 and in the of cells and the activity was cells with the RAR-selective in the of of of protein was and for TGase II expression by of TGase II with the RAR-selective retinoids and the RARα-antagonist that a signaling is involved in the of TGase II gene expression in SPOC-1 cells. To this the of the truncated RARα the of retinoids in SPOC-1 cells was In the cell line the dominant-negative activity and S. S. R. K. R. 1992; PubMed Scopus Google Scholar). To this has dominant-negative activity in SPOC-1 we these cells with the the gene and with which the truncated RARα cells and for expression of that the SPOC-1 cells of the the mRNA of the and TGase II expression in SPOC-1 cells by of the truncated RARα gene expression in SPOC-1 cells. SPOC-1 cells and and cells by a for RARα. of SRI-6751-84 and Ro40-6055 the of in and and SPOC-1 cells. cells for with retinoids and for are for of TGase II induction in and and SPOC-1 cells. with SRI-6751-84 at for and for TGase II expression by In this the induction of TGase II at SRI-6751-84 is that in the in to we analyzed the of the of and TGase II induction by In the and SPOC-1 the RAR-selective and RARα-selective retinoids induced activity to the In the the by the RAR-selective retinoid was whereas the by the RARα-selective retinoid was completely The of the induced by the RAR-selective retinoid to the that the mediated through is is in SRI-6751-84 induced TGase II well in and SPOC-1 cells. the induction of TGase II in SPOC-1 cells was less to SRI-6751-84 that in cells In SRI-6751-84 was to induce TGase II. is that for the the SPOC-1 between the of TGase II and have a role for TGase II in L. Thomazy V. Falus A. FEBS Lett. 1987; 224: 104-108Crossref PubMed Scopus (406) Google Scholar, 11Tarcsa E. Kedei N. Thomazy V. Fesus L. J. Biol. Chem. 1992; 267: 25648-25651Abstract Full Text PDF PubMed Google Scholar, 12Tomei L.D. Cope The of in Scholar). To the TGase II expression in SPOC-1 cells with the induction of we DNA fragmentation in of SPOC-1 cells with RAR-selective retinoid SRI-6751-84 for in the formation of a of DNA for cells L.D. Cope The of in whereas DNA was in the cells with the RXR-selective retinoid in cells. In the induction of DNA by SRI-6751-84 was by the with the RARα DNA in the SPOC-1 cells with the RAR-selective retinoid The formation of DNA was of with SRI-6751-84 The between the and the of the induction of TGase II expression and apoptosis by the retinoids suggest that these effects are mediated by the and in with the that TGase II plays a role in of DNA fragmentation in SPOC-1 and cells. SPOC-1 cells with RXR-selective retinoids RARα in the of the RAR-selective retinoid for and DNA was and by SPOC-1 SPOC-1 cells. with for we that and induce TGase II in several cell including George M.D. Jetten A.M. J. Cell Mol. Biol. 1992; PubMed Scopus Google Scholar). we to the induction of TGase II by is also by apoptosis in these cells. in of cells with in the formation of that the induction of apoptosis by is to SPOC-1 cells and the between the induction of TGase II and for the induction of apoptosis by retinoids in SPOC-1 the and SPOC-1 cells for the of apoptotic cells by apoptotic cells in and in with the RARα and the RAR-selective with the RXR-selective an increased of apoptotic cells was in with the RAR-selective retinoid the of an apoptotic cell at an of apoptosis in with In to the cell of the in the apoptotic cell is in and that the The is that of the in of the which of a SPOC-1 cell and an apoptotic cell at an of apoptosis in with RAR-selective retinoid for the and of the of which to the has been to induce TGase II gene expression in cell including several tracheobronchial epithelial cell T. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, M.D. Floyd E. Stein J.P. Jetten A.M. J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar, Rice R.H. Google Scholar, Biochem. PubMed Scopus Google Scholar, M. Fesus L. FEBS Lett. 1993; PubMed Scopus Google Scholar, George M.D. Jetten A.M. J. Cell Mol. Biol. 1992; PubMed Scopus Google Scholar). the of this has been is that retinoid receptors are implicated in this In the study, we the signaling that are involved in the increase of TGase II and apoptosis in rat epithelial SPOC-1 cells. We demonstrate that these cells express the retinoid RARα, RARγ, and retinoid also The effects of several receptor-selective an RARα and a truncated RARα gene in to identify the that are involved in these Our that the induction of TGase II gene expression in SPOC-1 cells by retinoids is mediated by a retinoid signaling that the RARα Several of this the RAR-selective retinoid is a potent inducer of TGase II retinoid to to receptors M. M. Google Scholar) and L. A. L. M. Science. 1992; PubMed Scopus Google Scholar). In the RXR-selective retinoid which to and formation of L. A. L. M. Science. 1992; PubMed Scopus Google Scholar) was to induce TGase II this retinoid activity in SPOC-1 cells as by to suggest that activation of plays a role in the induction of TGase II expression by the of activity through a with A.M. Cell. Full Text PDF PubMed Scopus Google Scholar) M. E. J. Mol. Cell. Biol. 1993; PubMed Scopus Google Scholar, M. M. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar). results suggest that activation of is a for the induction of TGase II by retinoids in tracheobronchial epithelial cells. is in with increased induction of TGase II in rat cells Biochem. PubMed Scopus Google Scholar) and Stein J.P. E.A. J.P. V. Thomazy V. Fesus L. in and Scholar) with expression the induction of TGase II in the cell line cells to an TGase II is induced by RXR-selective retinoids by RAR-selective ( J. A. the induction of TGase II by the RAR-selective retinoid was completely by the RARα The by which the has been the has been to with for to L. M. W. M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: PubMed Scopus Google Scholar). that in the of the RARα-antagonist the to to the L. M. W. M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: PubMed Scopus Google Scholar). the to induce the in the RARα that L. M. W. M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: PubMed Scopus Google Scholar). The of the of by this is in with this The to the that the activation mediated by is inhibited by the is by a little of the by L. M. W. M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: PubMed Scopus Google of the truncated RARα gene in SPOC-1 cells inhibited and the induction of TGase II by the RAR-selective retinoid The truncated the of by the RAR-selective retinoid by completely the by the RARα-selective retinoid results that TGase II induction through RARα. was that the truncated gene the differentiation in cells S. S. R. K. R. 1992; PubMed Scopus Google Scholar) and as a dominant-negative The by which the truncated RARα dominant-negative has to is able to in in R. S. J. Mol. Cell. Biol. 1994; PubMed Google Scholar) with a as the R. S. J. Mol. Cell. Biol. 1994; PubMed Google Scholar). has been that the as of a with A.M. Cell. Full Text PDF PubMed Scopus Google Scholar, M. E. J. Mol. Cell. Biol. 1993; PubMed Scopus Google Scholar, M. M. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar). The of the gene that a at is able to with the K. K. R.M. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google Scholar). Overexpression of the for with and the formation of the activation of gene that a of the by the RAR-selective retinoid and the of several in SPOC-1 cells. We have found that the effects of retinoids squamous are by A.M. Fujimoto W. K.W. S. K.J. Bernacki Saunders N.A. M.A. to Scholar). results that the by the is the retinoid signaling that the gene the type of the RARα-selective retinoid Ro40-6055 strongly induced TGase II expression retinoid was less which is to the of this RARα-selective retinoid to U. 1992; PubMed Scopus Google Scholar). the RARγ-selective retinoid CD437 was able to in SPOC-1 cells as as was to induce TGase II to of The of TGase II and to CD437 to between the of the response that activation by expression of was by in SPOC-1 results that an RARα-dependent an signaling is involved in the induction of TGase II expression by in SPOC-1 the of TGase II have to have implicated TGase II in the activation of (7Eitan S. Schwartz M. Science. 1993; 261: 106-108Crossref PubMed Scopus (126) Google Scholar) and S. Nara K. Rifkin D.B. J. Cell Biol. 1993; 121: 439-448Crossref PubMed Scopus (277) Google Scholar) and in signal transduction(9Nakaoka H. Perez D.M. Baek K.J. Das T. Husain A. Misono K. Im M.J. Graham R.M. Science. 1994; 264: 1593-1596Crossref PubMed Scopus (528) Google Scholar). In several cell types, the expression of TGase II is associated with the induction of L. Thomazy V. Falus A. FEBS Lett. 1987; 224: 104-108Crossref PubMed Scopus (406) Google Scholar, 11Tarcsa E. Kedei N. Thomazy V. Fesus L. J. Biol. Chem. 1992; 267: 25648-25651Abstract Full Text PDF PubMed Google Scholar, 12Tomei L.D. Cope The of in Scholar, M. M. J. Cell Biol. 1993; Google Scholar, H. D.M. 1992; PubMed Scopus Google Scholar, M. M. S. L. J. 1992; PubMed Scopus Google Scholar, 1990; PubMed Scopus Google Scholar). this is Our for the that retinoids induce apoptosis in rat and tracheobronchial epithelial cells as by the induction of DNA fragmentation and by the of cells with apoptotic In both SPOC-1 and this induction is by an increase in TGase II expression and and George M.D. Jetten A.M. J. Cell Mol. Biol. 1992; PubMed Scopus Google The by which retinoids induce apoptosis to with that for TGase II. was induced by the RAR-selective retinoid and inhibited by the RARα and by the of the truncated RARα gene in a manner similar to TGase II. have to the role is of TGase II in these results demonstrate that SPOC-1 cells are able to of growth squamous differentiation and of the of squamous differentiation and and TGase I and TGase II by is in squamous cell differentiation as by the of TGase I a squamous gene an that the formation of the cross-linked envelope(2Floyd E.E. Jetten A.M. Mol. Cell. Biol. 1989; 9: 4846-4851Crossref PubMed Scopus (103) Google Scholar, 6Marvin K.W. George M.D. Fujimoto W. Saunders N.A. Bernacki S. Jetten A.M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 11026-11030Crossref PubMed Scopus (146) Google Scholar). the is able to induce TGase II and an of cell apoptosis and to by retinoid signaling is by the in the of several as TGase I to the receptor-selective retinoids to that of TGase II and In to TGase II and the expression of TGase I and is by both the and RXR-selective retinoids and affected by the truncated RARα. ( and A. M. in of the of squamous differentiation and apoptosis and TGase I and TGase II by in epithelial squamous a between the of and has been that retinoids the at which cells squamous cell A.M. J. Natl. 1992; Scholar). The of apoptosis by which retinoids in these INTRODUCTIONTransglutaminases (EC 2.3.2.13, TGases) ( 1The abbreviations used are: TGasetransglutaminaseLUCluciferaseCATchloramphenicol acetyltransferaseRAall-trans-retinoic acidRARretinoic acid receptorRXRretinoid X receptorRARERAR response elementRXRERXR response elementTGFtransforming growth factor. )are Ca2+-dependent enzymes catalyzing the formation of ε(γ-glutamyl)lysine cross-links between polypeptide chains(1Folk J.E. Annu. Rev. Biochem. 1980; 49: 517-531Crossref PubMed Scopus (869) Google Scholar). Several members of this gene family have been identified including the type I (epidermal) TGase (2Floyd E.E. Jetten A.M. Mol. Cell. Biol. 1989; 9: 4846-4851Crossref PubMed Scopus (103) Google Scholar, 3Phillips M.A. Stewart B.E. Qin Q. Chakravarty R. Floyd E.E. Jetten A.M. Rice R.H. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 9333-9337Crossref PubMed Scopus (102) Google Scholar) and type II (tissue) TGase(4Chiocca E.A. Davies P.J. Stein J.P. J. Biol. Chem. 1988; 263: 11584-11589Abstract Full Text PDF PubMed Google Scholar, 5Ikura K. Nasu T. Yokota H. Tsuchiya Y. Sasaki R. Chiba H. Biochemistry. 1988; 27: 2898-2905Crossref PubMed Scopus (149) Google Scholar). TGase I is induced during squamous differentiation and plays a role in the formation of the cross-linked envelope(2Floyd E.E. Jetten A.M. Mol. Cell. Biol. 1989; 9: 4846-4851Crossref PubMed Scopus (103) Google Scholar, 6Marvin K.W. George M.D. Fujimoto W. Saunders N.A. Bernacki S. Jetten A.M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 11026-11030Crossref PubMed Scopus (146) Google Scholar). The function of TGase II is less well established. TGase II has been implicated in the activation of several cytokines (7Eitan S. Schwartz M. Science. 1993; 261: 106-108Crossref PubMed Scopus (126) Google Scholar, 8Kojima S. Nara K. Rifkin D.B. J. Cell Biol. 1993; 121: 439-448Crossref PubMed Scopus (277) Google Scholar) and in signal transduction(9Nakaoka H. Perez D.M. Baek K.J. Das T. Husain A. Misono K. Im M.J. Graham R.M. Science. 1994; 264: 1593-1596Crossref PubMed Scopus (528) Google Scholar). Expression of TGase II has been found in association with apoptosis in several cell types, and a role for TGase II in this process has been suggested(10Fesus L. Thomazy V. Falus A. FEBS Lett. 1987; 224: 104-108Crossref PubMed Scopus (406) Google Scholar, 11Tarcsa E. Kedei N. Thomazy V. Fesus L. J. Biol. Chem. 1992; 267: 25648-25651Abstract Full Text PDF PubMed Google Scholar, 12Tomei L.D. Cope The of in Scholar). is a process of cell and is in the of cells during in as well as in L.D. Cope The of in Scholar, Rev. 1980; PubMed Scopus Google Scholar). the function of TGase II in apoptosis has to has been that TGase II the of M. M. J. Cell Biol. 1993; Google has been to induce TGase II expression in a of cell E.A. Davies P.J. Stein J.P. J. Biol. Chem. 1988; 263: 11584-11589Abstract Full Text PDF PubMed Google Scholar, T. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, M.D. Floyd E. Stein J.P. Jetten A.M. J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar, Rice R.H. Google Scholar, Biochem. PubMed Scopus Google Scholar, M. Fesus L. FEBS Lett. 1993; PubMed Scopus Google Scholar, George M.D. Jetten A.M. J. Cell Mol. Biol. 1992; PubMed Scopus Google Scholar, Stein J.P. E.A. J.P. V. Thomazy V. Fesus L. in and Scholar). In the of TGase II expression by at the E.A. Davies P.J. Stein J.P. J. Biol. Chem. 1988; 263: 11584-11589Abstract Full Text PDF PubMed Google Scholar). is that of the effects of gene expression are mediated by the activation of retinoid The and Scholar). The and gene family and The and Scholar). are in a and cell The and and the expression of this study, we the retinoid signaling that are involved in the induction of TGase II and apoptosis in rat tracheobronchial epithelial SPOC-1 cells several retinoid receptor-selective and an We have also this through the expression of a truncated RARα that as a dominant-negative S. S. R. K. R. 1992; PubMed Scopus Google Scholar). Our results that the induction of TGase II gene expression and apoptosis by is mediated through a retinoid signaling that RARα.