MAPK signaling is required for retinoic acid (RA)-triggered G0 cell cycle arrest and cell differentiation, but the mechanism is not well defined. In this study, RA is found to cause MAPK activation with sustained association of RAF to MEK or ERK, leading to a MAPK-dependent accumulation of p21Waf1/Cip1 and binding to CDK2 blocking G1/S transition. BLR1, a chemokine receptor, was found to function as a critical component of RA-triggered MAPK signaling. Unlike wild-type parental cells, RA-treated BLR1 knock-out cells failed to show RAF and consequential MEK and ERK phosphorylation, failed to accumulate CDK inhibitors that control G1/S transition, and failed to differentiate and arrest in response to RA, whereas ectopically overexpressing BLR1 enhanced MAPK signaling and caused accelerated RA-induced differentiation and arrest. Ectopic overexpression of RAF enhanced BLR1 expression in response to RA, whereas inhibition of RAF or MEK by inhibitors or knockdown of RAF by short interfering RNA diminished RA-induced BLR1 expression and attenuated differentiation and growth arrest. Ectopic expression of the RAF CR3, the catalytically active domain, in the BLR1 knock-out restored RA-induced MAPK activation and the ability to differentiate and arrest, indicating that RAF effects MAPK signaling by BLR1 to propel differentiation/arrest. Taken together, RA induces cell differentiation and growth arrest through activation of a novel MAPK pathway with BLR1 as a critical component in a positive feedback mechanism that may contribute to the prolonged MAPK signaling propelling RA-induced cell cycle arrest and differentiation. MAPK signaling is required for retinoic acid (RA)-triggered G0 cell cycle arrest and cell differentiation, but the mechanism is not well defined. In this study, RA is found to cause MAPK activation with sustained association of RAF to MEK or ERK, leading to a MAPK-dependent accumulation of p21Waf1/Cip1 and binding to CDK2 blocking G1/S transition. BLR1, a chemokine receptor, was found to function as a critical component of RA-triggered MAPK signaling. Unlike wild-type parental cells, RA-treated BLR1 knock-out cells failed to show RAF and consequential MEK and ERK phosphorylation, failed to accumulate CDK inhibitors that control G1/S transition, and failed to differentiate and arrest in response to RA, whereas ectopically overexpressing BLR1 enhanced MAPK signaling and caused accelerated RA-induced differentiation and arrest. Ectopic overexpression of RAF enhanced BLR1 expression in response to RA, whereas inhibition of RAF or MEK by inhibitors or knockdown of RAF by short interfering RNA diminished RA-induced BLR1 expression and attenuated differentiation and growth arrest. Ectopic expression of the RAF CR3, the catalytically active domain, in the BLR1 knock-out restored RA-induced MAPK activation and the ability to differentiate and arrest, indicating that RAF effects MAPK signaling by BLR1 to propel differentiation/arrest. Taken together, RA induces cell differentiation and growth arrest through activation of a novel MAPK pathway with BLR1 as a critical component in a positive feedback mechanism that may contribute to the prolonged MAPK signaling propelling RA-induced cell cycle arrest and differentiation. MAPK 2The abbreviations used are: MAPKmitogen-activated protein kinaseERKextracellular signal-regulated kinaseMEKmitogen-activated protein kinase/extracellular signal-regulated kinase kinaseRAretinoic acidsiRNAshort interfering RNAEGFPenhanced green fluorescent proteinORFopen reading frameRTreverse transcriptionTPA12-O-tetradecanoylphorbol-13-acetateDCF5-(and-6)-chloromethyl-2′,7′-dichlorofluoresceinCDKcyclin-dependent kinaseRARretinoic acid-recepterRAREretinoic acid-response elementNBTnitro blue tetrazoliumNeoneomycinFTI-277farnesyltransferase inhibitor 277.2The abbreviations used are: MAPKmitogen-activated protein kinaseERKextracellular signal-regulated kinaseMEKmitogen-activated protein kinase/extracellular signal-regulated kinase kinaseRAretinoic acidsiRNAshort interfering RNAEGFPenhanced green fluorescent proteinORFopen reading frameRTreverse transcriptionTPA12-O-tetradecanoylphorbol-13-acetateDCF5-(and-6)-chloromethyl-2′,7′-dichlorofluoresceinCDKcyclin-dependent kinaseRARretinoic acid-recepterRAREretinoic acid-response elementNBTnitro blue tetrazoliumNeoneomycinFTI-277farnesyltransferase inhibitor 277. signaling was historically found as the effector of peptide growth factor-induced mitogenesis through the classical RAF/MEK/ERK axis. MAPK signaling has now been implicated in a wide variety of processes. Enigmatically it may also cause cell growth arrest and differentiation. How the signal is evoked to cause arrest and differentiation in contrast to mitogenesis is not well defined. Retinoic acid is a form of vitamin A that has known roles governing cell growth and differentiation in embryogenesis, nutrition, and chemotherapy of cancer. It can cause leukemic cell growth arrest and differentiation in a process that depends on sustained MAPK signaling (1Yen A. Roberson M.S. Varvayanis S. Lee A.T. Cancer Res. 1998; 58: 3163-3172PubMed Google Scholar, 2Yen A. Sturgill R. Varvayanis S. In Vitro Cell. Dev. Biol. 2000; 36: 249-255Crossref Google Scholar, 3Yen A. Williams M. Platko J.D. Der C. Hisaka M. Eur. J. Cell Biol. 1994; 65: 103-113PubMed Google Scholar), but the origin and regulation of that signaling are not well understood. It has thus been an elusive goal to find a paradigm that might rationalize how retinoic acid gives rise to the sustained MAPK signal that is needed to propel arrest and differentiation or a potential receptor that is seminal for that signal. mitogen-activated protein kinase extracellular signal-regulated kinase mitogen-activated protein kinase/extracellular signal-regulated kinase kinase retinoic acid short interfering RNA enhanced green fluorescent protein open reading frame reverse transcription 12-O-tetradecanoylphorbol-13-acetate 5-(and-6)-chloromethyl-2′,7′-dichlorofluorescein cyclin-dependent kinase retinoic acid-recepter retinoic acid-response element nitro blue tetrazolium neomycin farnesyltransferase inhibitor 277. mitogen-activated protein kinase extracellular signal-regulated kinase mitogen-activated protein kinase/extracellular signal-regulated kinase kinase retinoic acid short interfering RNA enhanced green fluorescent protein open reading frame reverse transcription 12-O-tetradecanoylphorbol-13-acetate 5-(and-6)-chloromethyl-2′,7′-dichlorofluorescein cyclin-dependent kinase retinoic acid-recepter retinoic acid-response element nitro blue tetrazolium neomycin farnesyltransferase inhibitor 277. BLR1, also known as CXCR5, is a putative serpentine heterotrimeric G protein-coupled CXC chemokine receptor. BLR1 was first found in a differential screen comparing malignant Burkitt lymphoma cells against Epstein-Barr virus-transformed normal B lymphocytes (4Dobner T. Wolf I. Emrich T. Lipp M. Eur. J. Immunol. 1992; 22: 2795-2799Crossref PubMed Scopus (129) Google Scholar). It was thus a potential determinant of the malignant phenotype of Burkitt lymphoma. The sequence is highly related to the interleukin-8 receptor. In humans BLR1 expression was originally found restricted to mature resting B cells and a subset of T-helper memory cells (5Forster R. Emrich T. Kremmer E. Lipp M. Blood. 1994; 84: 830-840Crossref PubMed Google Scholar, 6Kaiser E. Forster R. Wolf I. Ebensperger C. Kuehl W.M. Lipp M. Eur. J. Immunol. 1993; 23: 2532-2539Crossref PubMed Scopus (56) Google Scholar). The pathology of BLR1 knock-out mice suggested a role for BLR1 in lymphocyte migration and activation (7Forster R. Mattis A.E. Kremmer E. Wolf I. Brem G. Lipp M. Cell. 1996; 87: 1037-1047Abstract Full Text Full Text PDF PubMed Scopus (944) Google Scholar). However, its function is still unclear, and a clear demonstration of its ability to regulate cellular proliferation or differentiation remained elusive. Although originally implicated as a determinant of B cell malignancy, its cellular functions have not been elucidated. Expression of the BLR1 is induced by retinoic acid, and there is evidence such receptors can utilize MAPK signaling (8Battle T.E. Levine R.A. Yen A. Exp. Cell Res. 2000; 254: 287-298Crossref PubMed Scopus (34) Google Scholar, 9Battle T.E. Roberson M.S. Zhang T. Varvayanis S. Yen A. Eur. J. Cell Biol. 2001; 80: 59-67Crossref PubMed Scopus (36) Google Scholar). BLR1 may thus be of relevance to the mechanism of action of RA. As a known regulator of cell differentiation and proliferation, RA regulates BLR1 transcription through a novel retinoic acid-response element (RARE) that differs the The is a of the J. Yen A. Cell. Biol. PubMed Scopus Google Scholar). binding of and receptor to this of a and to of the of transcription the a active The in the BLR1 that it may have a role in the effects of retinoic acid on cell differentiation and the cell cells with RA expression of BLR1, enhanced ERK activation in the MAPK signaling and cell differentiation the and G0 cell cycle arrest (8Battle T.E. Levine R.A. Yen A. Exp. Cell Res. 2000; 254: 287-298Crossref PubMed Scopus (34) Google Scholar, 9Battle T.E. Roberson M.S. Zhang T. Varvayanis S. Yen A. Eur. J. Cell Biol. 2001; 80: 59-67Crossref PubMed Scopus (36) Google Scholar). In contrast to classical MAPK signaling in response to peptide growth a MAPK signal to MAPK signaling is prolonged and to differentiation and G0 arrest (1Yen A. Roberson M.S. Varvayanis S. Lee A.T. Cancer Res. 1998; 58: 3163-3172PubMed Google Scholar, 2Yen A. Sturgill R. Varvayanis S. In Vitro Cell. Dev. Biol. 2000; 36: 249-255Crossref Google Scholar, 3Yen A. Williams M. Platko J.D. Der C. Hisaka M. Eur. J. Cell Biol. 1994; 65: 103-113PubMed Google Scholar, Varvayanis S. Yen A. 2001; PubMed Scopus Google Scholar). MAPK signaling RA-induced differentiation indicating that it is for RA to differentiation and arrest. is with the paradigm that a short MAPK signal is a prolonged MAPK signal to differentiation growth arrest as by and S. C. J. 1992; PubMed Scopus Google in on the action of growth paradigm has been in RA-treated the of how the MAPK signal or is sustained in response to RA is still The of MAPK activation in response to RA a on Ectopic expression of BLR1 in in enhanced ERK activation with parental BLR1 may be a to RA-induced MAPK activation (8Battle T.E. Levine R.A. Yen A. Exp. Cell Res. 2000; 254: 287-298Crossref PubMed Scopus (34) Google Scholar, 9Battle T.E. Roberson M.S. Zhang T. Varvayanis S. Yen A. Eur. J. Cell Biol. 2001; 80: 59-67Crossref PubMed Scopus (36) Google Scholar). The BLR1 accelerated differentiation and G0 arrest in response to RA, a of RA-induced BLR1 expression with the known role of MAPK in propelling RA-induced cell differentiation and G0 arrest. BLR1 thus as an for the cell differentiation and cell cycle arrest to RA. a BLR1 knock-out of cells was in the cells with RA thus effects on BLR1 cells not BLR1 with RA, the knock-out or effects of of RA failed to or ERK activation in the knock-out Unlike cells, RA also failed to expression of p21Waf1/Cip1 and its binding to and the cells failed to cell cycle arrest or Ectopic expression of the RAF domain, is the catalytically active kinase of the in the BLR1 knock-out cells restored ERK activation and ability to differentiation and G0 arrest in response to retinoic of RAF in cells enhanced RA-induced BLR1 whereas of RAF attenuated BLR1 expression with feedback regulation of BLR1 RAF or MEK RA-induced ERK activation and BLR1 indicating that activation of BLR1 on of MAPK signaling. MAPK signaling was enhanced by RA-induced BLR1 a positive feedback thus propel BLR1 expression and MAPK a potential mechanism of prolonged BLR1 signaling that to the prolonged MAPK signal needed to cell differentiation and arrest in response to RA. with such a MEK was found to RAF The thus a function for BLR1 and its RAF signal in of RA-induced cell differentiation and G0 cell cycle arrest through a positive feedback the RAF/MEK/ERK MAPK signaling pathway by feedback of MAPK signaling to BLR1 expression and propel differentiation and arrest. a function for BLR1 and a clear demonstration of a role in cell differentiation and the cell against and and and and Cell the against was was retinoic acid, inhibitor farnesyltransferase inhibitor RAF inhibitor MEK inhibitor 12-O-tetradecanoylphorbol-13-acetate and was was was Cell cells and BLR1 BLR1 and in with in a and in by cells a of and the for as and RNA was cells by a to the for of BLR1 or or was with with a of or of the BLR1 sequence and The for BLR1 was used as a for The for and J. Yen A. Cell. Biol. PubMed Scopus Google Scholar). of BLR1 Cell a BLR1 knock-out cell a BLR1 was cells by The BLR1 a of of neomycin and kinase The BLR1 of a acid The first and by a the the of the known and putative the and the wild-type BLR1 in of a of the BLR1 in and of this sequence with by neomycin kinase RA the BLR1 is to a that the of BLR1 and In the BLR1 reading the kinase open reading frame has a by a of be As a in BLR1 knock-out cells the BLR1 protein of is and expression of and RA was cells, and in and for the was used to for The by a and the reverse BLR1 positive of the a the positive with a of for of positive a BLR1 and its sequence of a and with the for wild-type BLR1 positive with the of and for BLR1 or positive with of and for BLR1 with the used in the expression of a the short BLR1 and in with the wild-type BLR1 in The in the BLR1 knock-out cell was also by The BLR1 used in this is a of the positive of BLR1 a expression the Varvayanis S. Yen A. J. Cell. PubMed Scopus Google Scholar, Yen A. J. PubMed Scopus Google Scholar). The open reading frame of BLR1 was by and the of with a of as and reverse The A the BLR1 was to G to an for with a the The BLR1 with an was with a the with a of and reverse and and of the The G was to A to the wild-type BLR1 sequence with a the was by the was cells by with and to for The on the of by to a BLR1 expression of was by the of BLR1 sequence as a to a BLR1 not the The open reading frame was by cells with a of and reverse The was the of the and the of the was by and by cells with for and by The enhanced expression was by a The for the kinase of with an was by RNA cells with a of and reverse The was and of the a the of cells, and The was and BLR1 knock-out cells by and was to with for of the cells expression of the expression of BLR1 in BLR1 was by is the BLR1 was in and BLR1 by the with to with expression on sequence and sequence The RAF with a for of cells with a of of a RA was for the for or of against protein was in and of cell cell with or of RA was with the a the by and to for cells by and in of of and of to and for by as G. Yen A. Cancer Res. PubMed Scopus Google Scholar). the of cells of a for mature cells, was as the of cells of to of as A. J. Cell. PubMed Scopus Google Scholar, A. J. Res. PubMed Scopus Google Scholar). and by for the of cells the cell was by and cells by and in of of was and the was for an The to for positive was that of control cells Cell of cells in the cell cycle was by of to the of cells with as (1Yen A. Roberson M.S. Varvayanis S. Lee A.T. Cancer Res. 1998; 58: 3163-3172PubMed Google Scholar, A. J. Cell. PubMed Scopus Google Scholar). RA BLR1 RAF/MEK/ERK and p21Waf1/Cip1 Expression and to how of BLR1 RA-induced MAPK signaling and in the expression and of cyclin-dependent and the RA-induced first in As (8Battle T.E. Levine R.A. Yen A. Exp. Cell Res. 2000; 254: 287-298Crossref PubMed Scopus (34) Google Scholar, 9Battle T.E. Roberson M.S. Zhang T. Varvayanis S. Yen A. Eur. J. Cell Biol. 2001; 80: 59-67Crossref PubMed Scopus (36) Google Scholar), RA induces G0 cell cycle arrest and differentiation, by of mature is and cells are and of RA As in RA induced BLR1 expression with and still that to RA enhanced of RAF and induced of MEK and ERK not with RA in of not also for ERK activation in control RA also induced an in MEK expression that with MEK was RA regulate MEK expression in cells the ability of BLR1 knock-out cells to RA-induced G0 arrest and differentiation. expression of the in and in parental The of was the and BLR1 knock-out cells to of ERK, and p21Waf1/Cip1 expression to in response to RA for and and cells with RA for Expression of the RA-induced ERK activation and p21Waf1/Cip1 expression in The control is differentiation of and cells with RA for and as by by expression of in cells restored ability to differentiate in response to RA. The and are of cells with for and cells and of RA by Ectopic expression of in cells the of the BLR1 knock-out cells to G0 arrest. The and are The RA-induced MEK and ERK with with or with was of RA and through and to was with as a of RAF kinase in the of RA-treated The binding of or with was with binding in cells with of MEK ERK as ERK and to the A.E. J. Cell Biol. 2001; PubMed Scopus Google Scholar, C. J. Cell. Biol. 1992; PubMed Google Scholar, 1992; PubMed Scopus Google Scholar, C. G. G. A. J. J. Cell Biol. 1993; PubMed Scopus Google Scholar), ERK not with RA thus induced RAF/MEK/ERK with with an MAPK signaling J. 2000; PubMed Google Scholar). RA-induced MAPK signaling was with enhanced expression of the p21Waf1/Cip1 as by with a that RA induced activation of p21Waf1/Cip1 T. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). CDK2 not expression with RA The RA-induced of p21Waf1/Cip1 expression was by MEK the MEK in a that RA-induced ERK activation (1Yen A. Roberson M.S. Varvayanis S. Lee A.T. Cancer Res. 1998; 58: 3163-3172PubMed Google Scholar). The association of p21Waf1/Cip1 with CDK2 was also induced by RA, and this was by the of p21Waf1/Cip1 that with p21Waf1/Cip1 expression and its binding to CDK2 of RA thus on the RA-induced MAPK signaling. RA thus induced BLR1 a MAPK leading to enhanced p21Waf1/Cip1 expression and binding to p21Waf1/Cip1 and or by and in RA-treated cells not to the MAPK and and Cell in to the of RA-induced MAPK signaling and consequential cell differentiation and G0 cell cycle arrest on BLR1, BLR1 knock-out cells with a was used to the BLR1 the BLR1 the and the BLR1 the by by by the by in the of by as well as of the BLR1 and expression of the BLR1 in by was used to expression in of the cells BLR1 The knock-out cells, in growth or cell cycle with cells, as BLR1 is not in cells not the BLR1 are for RA response and to the role of BLR1 in RA-induced cell growth arrest and differentiation, expression of BLR1 in the BLR1 was by The show that expression of BLR1 in the BLR1 restored the expression of the differentiation of and G0 growth arrest in response to RA. how of BLR1 RA-induced MAPK signaling and p21Waf1/Cip1 binding to cells with RA and the consequential MAPK signaling and p21Waf1/Cip1 binding to CDK2 by and RA induced a of in BLR1 but not the response in a to a signal a of that and The cells RA in RAF The and of in the knock-out not show in with or RA this as was the for cells not the RA-induced of and ERK as this that RA-induced of MEK and ERK was also with RAF The of or ERK was in cells with In cells with BLR1 as (8Battle T.E. Levine R.A. Yen A. Exp. Cell Res. 2000; 254: 287-298Crossref PubMed Scopus (34) Google Scholar, 9Battle T.E. Roberson M.S. Zhang T. Varvayanis S. Yen A. Eur. J. Cell Biol. 2001; 80: 59-67Crossref PubMed Scopus (36) Google Scholar), accelerated RA-induced differentiation and G0 arrest, enhanced of and ERK In RA-treated RAF and MEK but not in the RA-treated cells with of RA to RAF activation for of a RAF/MEK/ERK signaling in RA-treated of RA-induced BLR1 expression and its RAF/MEK/ERK signaling in cells was with of RA-induced enhanced p21Waf1/Cip1 as by RA-induced p21Waf1/Cip1 binding to CDK2 in was also in cells with RA-treated cells failed to growth with cells BLR1 to its RA-induced expression in of a RAF/MEK/ERK signal and to expression of p21Waf1/Cip1 and its with the of BLR1 and its MAPK signal on RA-induced differentiation, cells, and cells with RA and for induced differentiation. was by expression of a cell and also by a for differentiation, RA induced expression of in but not in of expression the or cells, for control and RA-treated RA-induced expression was in The cells thus failed to the in response to RA, whereas expression was enhanced in cells, indicating that BLR1 expression induced by RA expression of the cell differentiation was also by a differentiation was by as G. Yen A. Cancer Res. PubMed Scopus Google Scholar). the for RA caused differentiation cells of in but not cells and of of BLR1 thus RA-induced differentiation in with cells that RA-induced cell cycle arrest also on BLR1, the of and cells in the and RA was by and for control and RA-treated and with the for differentiation, whereas cells and in with RA, the cells failed to G0 arrest. was enhanced for cells, with BLR1 expression enhanced induced differentiation and arrest (8Battle T.E. Levine R.A. Yen A. Exp. Cell Res. 2000; 254: 287-298Crossref PubMed Scopus (34) Google Scholar, 9Battle T.E. Roberson M.S. Zhang T. Varvayanis S. Yen A. Eur. J. Cell Biol. 2001; 80: 59-67Crossref PubMed Scopus (36) Google Scholar). The cell cycle the that the RA-treated cells to in contrast to the growth of the and cells in response to RA. As for RA-induced differentiation, of BLR1 RA-induced cell cycle arrest and growth BLR1 expression induced by RA was thus for RA to cause RAF/MEK/ERK MAPK signaling and cell differentiation and G0 cell cycle arrest. a paradigm RA induces BLR1 expression enhanced RAF with MEK and ERK in the prolonged MAPK signaling leading to accumulation of p21Waf1/Cip1 and its binding to that BLR1 and its RAF signaling through the MAPK pathway are critical to of cell differentiation and arrest in response to RA. RAF BLR1 and Ectopic Expression of RAF in BLR1 RA-induced MAPK and Cell and the for RAF in the differentiation in response to RA, the of RAF on RA-induced cell differentiation was cells with the to RAF and RA to to differentiation. The RA-induced ERK indicating that it was as Unlike control cells as the cells failed to differentiate in response to RA was by by a (1Yen A. Roberson M.S. Varvayanis S. Lee A.T. Cancer Res. 1998; 58: 3163-3172PubMed Google Scholar, 3Yen A. Williams M. Platko J.D. Der C. Hisaka M. Eur. J. Cell Biol. 1994; 65: 103-113PubMed Google Scholar). RAF also the enhanced ERK activation in cells, that ERK activation through RAF RAF and its consequential ERK activation thus are needed for RA-induced differentiation. The of RAF signaling of ability to differentiate is with the of RA-induced RAF in cells and its in cells that MEK is a activation of an of this is that MEK with the in of and the MEK RA-induced ERK that the was as The cells also failed to differentiate in response to RA as by the of as for RAF MEK the ERK activation in cells the of ERK activation on RAF and MEK Although have that RA not activation in cells, the of RA-induced differentiation on was to the that it not RA-induced differentiation S. S. T. T. T. Blood. 1994; 84: PubMed Google Scholar). The inhibitor was It on RA-induced ERK activation in or the cells ERK activation is enhanced of the BLR1 expression It also as on RA-induced differentiation Taken with the activation of MAPK signaling and of RA-induced differentiation to BLR1 have The of for MAPK activation is with in to that activation of the RAF/MEK/ERK pathway leading to differentiation is of activation M. M. G. S. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In RAF has also been found to have through MEK and ERK, and in it can through a indicating the to the RAF/MEK/ERK signaling for cell it can J. Zhang T. S. A. 2001; PubMed Scopus Google Scholar). As used in the of the inhibitors by cell growth or as for this (1Yen A. Roberson M.S. Varvayanis S. Lee A.T. Cancer Res. 1998; 58: 3163-3172PubMed Google Scholar). RAF or MEK but not also RA-induced BLR1 expression RA-induced BLR1 expression thus was by MAPK signaling. MEK RA-induced of RAF in and in cells there is BLR1 expression The may a positive feedback BLR1 MEK and ERK activation BLR1 expression to a feedback in prolonged MAPK signaling. In this as was in the the and cause of RAF as was the be with diminished RAF knockdown of was that expression was by to RA-induced BLR1 expression was diminished by knockdown of but not by control with cells the the knockdown cells and the or control The knockdown thus the and the that overexpression of RAF RA-induced BLR1 that the RAF with the and The also as a of RA-induced BLR1 expression was in the the or control cells, the As overexpression of enhanced differentiation and growth arrest not diminished RA-induced BLR1 whereas overexpressing enhanced RA-induced BLR1 BLR1 through a MAPK there is an positive feedback RA-induced BLR1 of or for cells, and or with RA. RA-induced BLR1 expression by The BLR1 expression was by The of RA-induced differentiation on BLR1 and its signaling a of expression of in cells can ERK activation and cell differentiation in response to RA. with the domain, is the catalytically active kinase of the S. A. 1998; PubMed Scopus Google Scholar, G. I. J. Biol. 1994; Full Text PDF PubMed Scopus Google Scholar, G. M. T. Cell. Biol. PubMed Scopus Google Scholar, Cell. Biol. PubMed Scopus Google Scholar). Expression of the in was by ERK activation in response to RA was restored in the cells with parental cells indicating ERK signaling is in The that the ERK activation was with cells The thus the of RA-induced MAPK RA-induced p21Waf1/Cip1 expression was also restored in cells with parental cells in response to RA was restored in cells in contrast to parental that to differentiate was by by The and of differentiation of with RA-induced p21Waf1/Cip1 and the ability to the cells also the ability to cell cycle arrest in response to RA Ectopic expression of RAF in cells thus restored ERK activation and cell differentiation and G0 arrest in response to RA. the MAPK signaling to RA-induced BLR1 expression is with of that of the kinase of the kinase T. M. M. A. Cell. Biol. 1996; PubMed Scopus Google Scholar), binding of to but that its not in response to J. M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). have that can be in a and indicating that binding is not a for activation Cell. Biol. PubMed Scopus Google Scholar). that in was a positive regulator of activation Cell. Biol. 1998; PubMed Scopus Google Scholar). It is thus that the function of is and on cell In it may function the now classical and the may on the of the signaling for a The of to the may thus be an determinant of how functions and the role of The the of RA-induced BLR1 MAPK is not and is with binding to MEK and ERK and that this was on RA. RA, there was also of MAPK signaling in cells the not indicating the for RA-induced to an active signaling and the cellular ability to growth arrest and In this that whereas show that BLR1 signaling is a critical determinant of cells arrest and differentiate in response to RA, it is not the cells, have enhanced MAPK not differentiate with RA, indicating that BLR1 and its RAF/MEK/ERK signaling are a critical component of the induced by RA, it is not the of the to BLR1 signaling and cellular are It that overexpression of BLR1 RA-induced arrest and differentiation that of the receptor is In the of the in is not a known in and was by and by RA or of or BLR1 expression by not to the potential of in the signaling in the cellular found that of RA-induced phosphorylation, ERK and arrest and differentiation. The of is with the J. M. Cell. Full Text Full Text PDF PubMed Scopus Google of its in the of the signaling and are in the of In and ERK activation in a feedback to BLR1 expression that MAPK signaling. of MAPK signaling thus be with enhanced CDK inhibitors and leading to growth arrest and cell differentiation. The of its on and signaling is BLR1 expression and its RAF signaling thus a critical function in RA-induced cell differentiation and G0 arrest, a function on proliferation to the of its are to for
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