Home LiteratureArticle Details
PMID: 9032283 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Retinoic acid blocks adipogenesis by inhibiting C/EBPbeta-mediated transcription.

Molecular and cellular biology ·Vol. 17 ·No. 3 ·1997-03-00 ·Pages 1552-61

Schwarz EJ, Reginato MJ, Shao D, Krakow SL, Lazar MA

Abstract

Adipocyte differentiation is thought to involve sequential induction of the transcription factors C/EBPbeta, peroxisome proliferator-activated receptor gamma (PPARgamma), and C/EBPalpha. C/EBPalpha expression is both necessary and sufficient for adipocyte differentiation. Here we report that ectopic expression of either C/EBPalpha or C/EBPbeta induces PPARgamma expression and adipogenesis and that retinoic acid (RA) completely inhibits adipogenesis by either form of C/EBP. In studies of normal preadipocytes, RA does not prevent C/EBPbeta induction but blocks induction of PPARgamma, C/EBPalpha, and adipogenesis. In transient transfection studies, liganded RA receptor (RAR) specifically blocks transcriptional activation by either C/EBPalpha or C/EBPbeta. These results strongly suggest that C/EBPalpha substitutes for C/EBPbeta to induce adipocyte differentiation and that liganded RAR inhibits adipogenesis by blocking C/EBPbeta-mediated induction of downstream genes.

MeSH Terms
3T3 Cells Adipocytes/cytology,drug effects Animals CCAAT-Enhancer-Binding Proteins Cell Differentiation DNA-Binding Proteins/genetics,physiology Gene Expression Regulation/drug effects,physiology Ligands Mice Nuclear Proteins/genetics,physiology Receptors, Cytoplasmic and Nuclear/genetics Receptors, Retinoic Acid/physiology Recombinant Fusion Proteins Transcription Factors/genetics Transcription, Genetic/drug effects,physiology Transcriptional Activation Transfection Tretinoin/pharmacology
Chemicals
CCAAT-Enhancer-Binding Proteins DNA-Binding Proteins Ligands Nuclear Proteins Receptors, Cytoplasmic and Nuclear Receptors, Retinoic Acid Recombinant Fusion Proteins Transcription Factors Tretinoin
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Schwarz E J
Department of Medicine, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Reginato M J
Shao D
Krakow S L
Lazar M A
References (72)
72 references, click to expand
  1. Mutations of the rat growth hormone promoter which increase and decrease response to thyroid hormone define a consensus thyroid hormone response element.
    Mol Endocrinol. 1989 Dec;3(12):1996-2004 PMID: 2628734
  2. Improved retroviral vectors for gene transfer and expression.
    Biotechniques. 1989 Oct;7(9):980-2, 984-6, 989-90 PMID: 2631796
  3. A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family.
    EMBO J. 1990 Jun;9(6):1897-906 PMID: 2112087
  4. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily.
    Science. 1995 Nov 24;270(5240):1354-7 PMID: 7481822
  5. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma.
    Cell. 1995 Dec 1;83(5):803-12 PMID: 8521497
  6. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation.
    Cell. 1995 Dec 1;83(5):813-9 PMID: 8521498
  7. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors.
    Cell. 1996 May 3;85(3):403-14 PMID: 8616895
  8. DNA binding specificity of the CCAAT/enhancer-binding protein transcription factor family.
    J Biol Chem. 1996 Feb 16;271(7):3891-6 PMID: 8632009
  9. Distinct stages in adipogenesis revealed by retinoid inhibition of differentiation after induction of PPARgamma.
    Mol Cell Biol. 1996 Apr;16(4):1567-75 PMID: 8657131
  10. Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids.
    Mol Cell Biol. 1996 Aug;16(8):4128-36 PMID: 8754811
  11. Transcription. A growing coactivator network.
    Nature. 1996 Sep 5;383(6595):22-3 PMID: 8779707
  12. An amino-terminal c-myc domain required for neoplastic transformation activates transcription.
    Mol Cell Biol. 1990 Nov;10(11):5914-20 PMID: 2233723
  13. CCAAT/enhancer binding protein gene promoter: binding of nuclear factors during differentiation of 3T3-L1 preadipocytes.
    Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2593-7 PMID: 2006196
  14. The functionally active IE2 immediate-early regulatory protein of human cytomegalovirus is an 80-kilodalton polypeptide that contains two distinct activator domains and a duplicated nuclear localization signal.
    J Virol. 1991 Jul;65(7):3839-52 PMID: 1645794
  15. The molecular basis for inhibition of adipose conversion of murine 3T3-L1 cells by retinoic acid.
    Differentiation. 1990 Nov;45(2):119-27 PMID: 1982997
  16. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells.
    Genes Dev. 1991 Sep;5(9):1538-52 PMID: 1840554
  17. A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA.
    Cell. 1991 Nov 1;67(3):569-79 PMID: 1934061
  18. RXR beta: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements.
    Cell. 1991 Dec 20;67(6):1251-66 PMID: 1662118
  19. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling.
    Nature. 1992 Jan 30;355(6359):446-9 PMID: 1310351
  20. Enhancement of adipocyte differentiation by an insulin-sensitizing agent.
    Mol Pharmacol. 1992 Feb;41(2):393-8 PMID: 1538716
  21. Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors.
    EMBO J. 1992 Mar;11(3):1025-33 PMID: 1372244
  22. Antisense CCAAT/enhancer-binding protein RNA suppresses coordinate gene expression and triglyceride accumulation during differentiation of 3T3-L1 preadipocytes.
    Genes Dev. 1992 Apr;6(4):533-44 PMID: 1373117
  23. RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors.
    EMBO J. 1992 Apr;11(4):1409-18 PMID: 1314167
  24. RAR gamma 2 expression is regulated through a retinoic acid response element embedded in Sp1 sites.
    Mol Cell Biol. 1992 Jul;12(7):2976-85 PMID: 1320193
  25. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors.
    Nature. 1992 Aug 27;358(6389):771-4 PMID: 1324435
  26. A mutated retinoic acid receptor-alpha exhibiting dominant-negative activity alters the lineage development of a multipotent hematopoietic cell line.
    Genes Dev. 1992 Dec;6(12A):2258-69 PMID: 1334022
  27. Functional inhibition of retinoic acid response by dominant negative retinoic acid receptor mutants.
    Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2989-93 PMID: 8096643
  28. Antidiabetic agent pioglitazone enhances adipocyte differentiation of 3T3-F442A cells.
    Am J Physiol. 1993 Jun;264(6 Pt 1):C1600-8 PMID: 8333508
  29. Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation.
    J Biol Chem. 1993 Aug 5;268(22):16265-9 PMID: 8344913
  30. CCAAT/enhancer binding protein alpha (C/EBP alpha) undifferentiated protein: a developmentally regulated nuclear protein that binds to the C/EBP alpha gene promoter.
    Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7312-6 PMID: 8346250
  31. Retinoic acid receptor gamma 2 gene expression is up-regulated by retinoic acid in 3T3-L1 preadipocytes.
    Biochem J. 1993 Aug 1;293 ( Pt 3):807-12 PMID: 8394693
  32. CCAAT/enhancer-binding protein mRNA is translated into multiple proteins with different transcription activation potentials.
    Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8219-23 PMID: 8367486
  33. A 30-kDa alternative translation product of the CCAAT/enhancer binding protein alpha message: transcriptional activator lacking antimitotic activity.
    Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9606-10 PMID: 8415748
  34. Nuclear receptor/AP-1 interaction.
    Endocr Rev. 1993 Oct;14(5):651-8 PMID: 8262011
  35. Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor.
    Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):752-6 PMID: 8290595
  36. Three levels of functional interaction determine the activity of CCAAT/enhancer binding protein-alpha on the serum albumin promoter.
    Genes Dev. 1994 Feb 1;8(3):350-62 PMID: 8314088
  37. Peroxisome proliferator and retinoid signaling pathways co-regulate preadipocyte phenotype and survival.
    Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1786-90 PMID: 8127882
  38. Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription.
    Science. 1994 Jun 3;264(5164):1455-8 PMID: 8197458
  39. Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation.
    Endocrinology. 1994 Aug;135(2):798-800 PMID: 8033830
  40. The C/EBP family of proteins distorts DNA upon binding but does not introduce a large directed bend.
    J Biol Chem. 1994 Sep 23;269(38):23553-62 PMID: 8089123
  41. CCAAT/enhancer binding protein alpha is sufficient to initiate the 3T3-L1 adipocyte differentiation program.
    Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8757-61 PMID: 8090719
  42. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.
    Genes Dev. 1994 May 15;8(10):1224-34 PMID: 7926726
  43. Endogenous retinoid X receptors can function as hormone receptors in pituitary cells.
    Mol Cell Biol. 1994 Nov;14(11):7105-10 PMID: 7935425
  44. Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding.
    Nature. 1994 Oct 6;371(6497):528-31 PMID: 7935766
  45. Activation function 2 (AF-2) of retinoic acid receptor and 9-cis retinoic acid receptor: presence of a conserved autonomous constitutive activating domain and influence of the nature of the response element on AF-2 activity.
    EMBO J. 1994 Nov 15;13(22):5370-82 PMID: 7957103
  46. Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells.
    Genes Dev. 1994 Jul 15;8(14):1654-63 PMID: 7958846
  47. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor.
    Cell. 1994 Dec 30;79(7):1147-56 PMID: 8001151
  48. PPAR gamma 2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene.
    Mol Cell Biol. 1995 Jan;15(1):351-7 PMID: 7799943
  49. Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors.
    Mol Cell Biol. 1995 Feb;15(2):943-53 PMID: 7823959
  50. Negative transcriptional regulation by nuclear receptors.
    Semin Cancer Biol. 1994 Oct;5(5):347-59 PMID: 7849263
  51. Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins.
    Genes Dev. 1995 Jan 15;9(2):168-81 PMID: 7531665
  52. Retinoic acid prevents downregulation of ras recision gene/lysyl oxidase early in adipocyte differentiation.
    Differentiation. 1994 Nov;58(1):47-52 PMID: 7867896
  53. Targeting expression of a dominant-negative retinoic acid receptor mutant in the epidermis of transgenic mice results in loss of barrier function.
    Genes Dev. 1995 Feb 1;9(3):317-29 PMID: 7867929
  54. Interaction of thyroid-hormone receptor with a conserved transcriptional mediator.
    Nature. 1995 Mar 2;374(6517):91-4 PMID: 7870181
  55. The N-terminal part of TIF1, a putative mediator of the ligand-dependent activation function (AF-2) of nuclear receptors, is fused to B-raf in the oncogenic protein T18.
    EMBO J. 1995 May 1;14(9):2020-33 PMID: 7744009
  56. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma).
    J Biol Chem. 1995 Jun 2;270(22):12953-6 PMID: 7768881
  57. CRP2 (C/EBP beta) contains a bipartite regulatory domain that controls transcriptional activation, DNA binding and cell specificity.
    EMBO J. 1995 Jul 3;14(13):3170-83 PMID: 7621830
  58. Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor.
    EMBO J. 1995 Aug 1;14(15):3741-51 PMID: 7641693
  59. Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms.
    Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7921-5 PMID: 7644514
  60. Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta.
    Mol Cell Biol. 1995 Sep;15(9):4971-9 PMID: 7651415
  61. Impaired energy homeostasis in C/EBP alpha knockout mice.
    Science. 1995 Aug 25;269(5227):1108-12 PMID: 7652557
  62. Negative cross-talk between RelA and the glucocorticoid receptor: a possible mechanism for the antiinflammatory action of glucocorticoids.
    Mol Endocrinol. 1995 Apr;9(4):401-12 PMID: 7659084
  63. A transcriptional co-repressor that interacts with nuclear hormone receptors.
    Nature. 1995 Oct 5;377(6548):454-7 PMID: 7566127
  64. Conditional ectopic expression of C/EBP beta in NIH-3T3 cells induces PPAR gamma and stimulates adipogenesis.
    Genes Dev. 1995 Oct 1;9(19):2350-63 PMID: 7557387
  65. Role of CBP/P300 in nuclear receptor signalling.
    Nature. 1996 Sep 5;383(6595):99-103 PMID: 8779723
  66. p300 is a component of an estrogen receptor coactivator complex.
    Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11540-5 PMID: 8876171
  67. CCAAT/enhancer binding protein-alpha amino acid motifs with dual TBP and TFIIB binding ability co-operate to activate transcription in both yeast and mammalian cells.
    EMBO J. 1995 Sep 1;14(17):4318-28 PMID: 7556073
  68. Differential activation of peroxisome proliferator-activated receptors by eicosanoids.
    J Biol Chem. 1995 Oct 13;270(41):23975-83 PMID: 7592593
  69. Transcriptional regulation of gene expression during adipocyte differentiation.
    Annu Rev Biochem. 1995;64:345-73 PMID: 7574486
  70. Differentiation of 3T3-F442A cells into adipocytes is inhibited by retinoic acid.
    Differentiation. 1982;23(2):164-9 PMID: 7166214
  71. Transcription activation by the adenovirus E1a protein.
    Nature. 1989 Mar 2;338(6210):39-44 PMID: 2521923
  72. Differentiation-induced gene expression in 3T3-L1 preadipocytes: CCAAT/enhancer binding protein interacts with and activates the promoters of two adipocyte-specific genes.
    Genes Dev. 1989 Sep;3(9):1323-35 PMID: 2606350
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.17.3.1552
Published
1997-03-00
Pages
1552-61
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC231881
Subset
IM
Grants
NIGMS NIH HHS · 5F31 GM15677 · United States
NIDDK NIH HHS · DK49210 · United States
NIDDK NIH HHS · DK49780 · United States
External Links
PubMed source DOI: 10.1128/MCB.17.3.1552 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2