Rat hepatic stellate cells acquire retinoid responsiveness after activation in vitro by post-transcriptional regulation of retinoic acid receptor alpha gene expression

2007 ◽  
Vol 465 (2) ◽  
pp. 370-379 ◽  
Author(s):  
Yoshihiro Mezaki ◽  
Kiwamu Yoshikawa ◽  
Noriko Yamaguchi ◽  
Mitsutaka Miura ◽  
Katsuyuki Imai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Retinoic Acid ◽  
Hepatic Stellate Cells ◽  
Retinoic Acid Receptor ◽  
Stellate Cells ◽  
Retinoic Acid Receptor Alpha ◽  
Alpha Gene ◽  
Post Transcriptional Regulation

Retinoic acid signaling sensitizes hepatic stellate cells to NK cell killing via upregulation of NK cell activating ligand RAE1

2007 ◽  
Vol 293 (4) ◽  
pp. G809-G816 ◽  
Author(s):  
Svetlana Radaeva ◽  
Lei Wang ◽  
Sergei Radaev ◽  
Won-Il Jeong ◽  
Ogyi Park ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Hepatic Stellate Cells ◽  
Nk Cell ◽  
Retinoic Acid Receptor ◽  
Neutralizing Antibody ◽  
Stellate Cells ◽  
Cell Killing ◽  
Liver Fibrogenesis ◽  
Vitro Model

Hepatic stellate cells (HSCs) store 75% of the body's supply of vitamin A (retinol) and play a key role in liver fibrogenesis. During liver injury, HSCs become activated and susceptible to natural killer (NK) cell killing due to increased expression of the NK cell activating ligand retinoic acid early inducible gene 1 (RAE-1). To study the mechanism by which RAE-1 is upregulated in HSCs during activation, an in vitro model of cultured mouse HSCs was employed. RAE-1 was detected at low levels in quiescent HSCs but upregulated in 4- and 7-day cultured HSCs (early activated HSCs), whereas 21-day cultured HSCs (fully activated HSCs) lost RAE-1 expression. High levels of RAE-1 in 4- and 7-day cultured HSCs correlated with their susceptibility to NK cell killing, which was diminished by treatment with RAE-1 neutralizing antibody. Furthermore, retinoic acid (RA) and retinal dehydrogenase (Raldh) levels were upregulated in early activated HSCs compared with quiescent or fully activated HSCs. Blocking RA synthesis by the Raldh inhibitor or blocking RA signaling by the retinoic acid receptor antagonist abolished upregulation of RAE-1 whereas treatment with RA induced RAE-1 expression in HSCs. In conclusion, during activation, HSCs lose retinol, which is either secreted out or oxidized into RA; the latter stimulates RAE-1 expression and sensitizes early activated HSCs to NK cell killing. In contrast, fully activated HSCs become resistant to NK cell killing because of lack of RAE1 expression, leading to chronic liver fibrosis and disease.

scholarly journals Pharmacological Activity of Retinoic Acid Receptor Alpha-Selective Antagonists in Vitro and in Vivo

2013 ◽  
Vol 4 (5) ◽  
pp. 446-450 ◽  
Author(s):  
Sanny S. W. Chung ◽  
Rebecca A. D. Cuellar ◽  
Xiangyuan Wang ◽  
Peter R. Reczek ◽  
Gunda I. Georg ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Pharmacological Activity ◽  
Retinoic Acid Receptor ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Receptor ◽  
Receptor Alpha ◽  
Selective Antagonists

scholarly journals Identification of DNA rearrangements at the retinoic acid receptor- alpha (RAR-alpha) locus in all patients with acute promyelocytic leukemia (APL) and mapping of APL breakpoints within the RAR-alpha second intron. Italian Cooperative Study Group "GIMEMA"

Blood ◽  
1992 ◽  
Vol 79 (12) ◽  
pp. 3331-3336 ◽  
Author(s):  
D Diverio ◽  
F Lo Coco ◽  
F D'Adamo ◽  
A Biondi ◽  
M Fagioli ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Genomic Alteration ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Receptor ◽  
Receptor Alpha ◽  
Significant Difference ◽  
Alpha Gene

Seventy patients with acute promyelocytic leukemia (APL) were characterized at the DNA level using genomic retinoic acid receptor- alpha (RAR-alpha) probes on Southern blot experiments. Sixty-two cases were defined as M3 according to the French-American-British (FAB) criteria, and eight had a diagnosis of microgranular or variant (M3v) APL. The use of two restriction enzymes and three probes exploring the second intron of the RAR-alpha gene allowed us to detect specific abnormal DNA fragments in every case, with clustering of rearrangements within the 20-kb intronic region between RAR-alpha exons II and III. A more detailed mapping of APL breakpoints was performed in 52 cases in which three EcoRI subregions of the RAR-alpha second intron were analyzed with corresponding probes. Comparison of clinical and hematological features in the three subgroups of patients with distinct RAR-alpha breakpoints did not show significant differences regarding age, peripheral blood (PB) counts, presence of coagulopathy, or FAB classification (M3 v M3v). Interestingly, a significant difference was observed in the M/F ratio of the three subgroups, with a higher incidence of rearrangements at the 5′ end of the RAR-alpha second intron in female patients, and more frequent 3′ breakpoints in males. The results of this study indicate that a unique genomic alteration consistently occurs on the 17q- derivative of the APL specific t(15;17) aberration. Moreover, the clinical relevance of RAR-alpha gene analysis both at diagnosis and in follow-up studies is further emphasized.

Retinoic acid-resistant HL-60 cells exclusively contain mutant retinoic acid receptor-alpha

Blood ◽  
1994 ◽  
Vol 83 (11) ◽  
pp. 3298-3302 ◽  
Author(s):  
YP Li ◽  
F Said ◽  
RE Gallagher
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Hot Spot ◽  
Dominant Negative ◽  
Reaction Products ◽  
Retinoic Acid Receptor Alpha ◽  
Restriction Endonuclease Site ◽  
Acid Receptor ◽  
Receptor Alpha ◽  
Alpha Gene

Abstract Sequence analysis of the retinoic acid receptor-alpha (RAR alpha) gene from a subline of HL-60 cells (RA-res) stably resistant to all-trans retinoic acid (RA) disclosed a single-base change in codon number 411, the same C to T transition previously reported in an independently selected HL-60 RA resistant clone by Robertson et al (Blood 80:1885, 1992). This mutation eliminates a FokI restriction endonuclease site. Using primers framing this mutation in exon 9 of the RAR alpha gene, we showed that polymerase chain reaction products amplified from either mRNA or genomic DNA templates from the RA-res subline were completely resistant to FokI digestion whereas those from wild-type (wt) HL-60 cells could be digested to completion. The lack of a normal allele in the RA-res cells was confirmed by mixing experiments and hybridization analyses. Southern blot analysis of DNA from the RA-res and wt cells versus control placental DNA indicated that the RAR alpha gene is not haploid. The independent isolation of the same RAR alpha mutation in different laboratories suggests either that the mutation exits in a small subpopulation in the wt line or that this is a mutational “hot spot.” Furthermore, the results indicate that if a dominant negative mode of resistance is involved in the RA-res subline, this must involve interference with the function of heterologous receptor proteins such as the retinoid X receptors. The lack of any normal RAR alpha in this subline may facilitate studies of the mode of action of retinoids.

scholarly journals Dynamic Changes in Function and Proteomic Composition of Extracellular Vesicles from Hepatic Stellate Cells during Cellular Activation

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 290 ◽  
Author(s):  
Xinlei Li ◽  
Ruju Chen ◽  
Sherri Kemper ◽  
David R Brigstock
Keyword(s):  
Gene Expression ◽  
Hepatic Stellate Cells ◽  
Fold Increase ◽  
Stellate Cells ◽  
Extracellular Vesicle ◽  
Fine Tuning ◽  
Shared Identity ◽  
Cellular Source

During chronic liver injury, hepatic stellate cells (HSC) undergo activation and are the principal cellular source of collagenous scar. In this study, we found that activation of mouse HSC (mHSC) was associated with a 4.5-fold increase in extracellular vesicle (EV) production and that fibrogenic gene expression (CCN2, Col1a1) was suppressed in Passage 1 (P1; activated) mHSC exposed to EVs from Day 4 (D4; relatively quiescent) mHSC but not to EVs from P1 mHSC. Conversely, gene expression (CCN2, Col1a1, αSMA) in D4 mHSC was stimulated by EVs from P1 mHSC but not by EVs from D4 mHSC. EVs from Day 4 mHSC contained only 46 proteins in which histones and keratins predominated, while EVs from P1 mHSC contained 337 proteins and these were principally associated with extracellular spaces or matrix, proteasome, collagens, vesicular transport, metabolic enzymes, ribosomes and chaperones. EVs from the activated LX-2 human HSC (hHSC) line also promoted fibrogenic gene expression in D4 mHSC in vitro and contained 524 proteins, many of which shared identity or had functional overlap with those in P1 mHSC EVs. The activation-associated changes in production, function and protein content of EVs from HSC likely contribute to the regulation of HSC function in vivo and to the fine-tuning of fibrogenic pathways in the liver.

scholarly journals Identification of DNA rearrangements at the retinoic acid receptor- alpha (RAR-alpha) locus in all patients with acute promyelocytic leukemia (APL) and mapping of APL breakpoints within the RAR-alpha second intron. Italian Cooperative Study Group "GIMEMA"

Blood ◽  
1992 ◽  
Vol 79 (12) ◽  
pp. 3331-3336 ◽  
Author(s):  
D Diverio ◽  
F Lo Coco ◽  
F D'Adamo ◽  
A Biondi ◽  
M Fagioli ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Genomic Alteration ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Receptor ◽  
Receptor Alpha ◽  
Significant Difference ◽  
Alpha Gene

Abstract Seventy patients with acute promyelocytic leukemia (APL) were characterized at the DNA level using genomic retinoic acid receptor- alpha (RAR-alpha) probes on Southern blot experiments. Sixty-two cases were defined as M3 according to the French-American-British (FAB) criteria, and eight had a diagnosis of microgranular or variant (M3v) APL. The use of two restriction enzymes and three probes exploring the second intron of the RAR-alpha gene allowed us to detect specific abnormal DNA fragments in every case, with clustering of rearrangements within the 20-kb intronic region between RAR-alpha exons II and III. A more detailed mapping of APL breakpoints was performed in 52 cases in which three EcoRI subregions of the RAR-alpha second intron were analyzed with corresponding probes. Comparison of clinical and hematological features in the three subgroups of patients with distinct RAR-alpha breakpoints did not show significant differences regarding age, peripheral blood (PB) counts, presence of coagulopathy, or FAB classification (M3 v M3v). Interestingly, a significant difference was observed in the M/F ratio of the three subgroups, with a higher incidence of rearrangements at the 5′ end of the RAR-alpha second intron in female patients, and more frequent 3′ breakpoints in males. The results of this study indicate that a unique genomic alteration consistently occurs on the 17q- derivative of the APL specific t(15;17) aberration. Moreover, the clinical relevance of RAR-alpha gene analysis both at diagnosis and in follow-up studies is further emphasized.

Sign in / Sign up

Export Citation Format

Share Document