Integration of the Activation of the Human Hyaluronan Synthase 2 Gene Promoter by Common Cofactors of the Transcription Factors Retinoic Acid Receptor and Nuclear Factor κB

The rat α-fetoprotein (afp) gene is controlled by three enhancers whose function depends on their interaction with liver-enriched transcription factors. The afp enhancer III, located at −6kb, is composed of three regions that act in synergy. Two of these regions, called s1 and s2, contain a putative binding site for hepatocyte nuclear factor-6 (HNF-6). This factor is the prototype of the ONECUT family of cut-homoeodomain proteins and is a known regulator of liver gene expression in adults and during development. We show here that the two splicing isoforms of HNF-6 bind to a site in the s1 region and in the s2 region. The core sequence of the s1 site corresponds to none of the known HNF-6 binding sites. Nevertheless, the binding properties of the s1 site are identical with those of the s2 site and of previously characterized HNF-6 binding sequences. The HNF-6 consensus should therefore be rewritten as DRRTCVATND. Binding of HNF-6 to the s1 and s2 sites requires both the cut and the homoeo domains, is co-operative and induces DNA bending. HNF-6 strongly stimulates the activity of the afp enhancer III in transient transfection experiments. This effect requires the stereo-specific alignment of the two HNF-6 sites. Moreover, HNF-6 stimulates the enhancer in synergy with the retinoic-acid-receptor-related orphan receptor α (RORα), which binds to a neighbouring site in the s1 region. Thus expression of the afp gene requires functional interactions between HNF-6 molecules and between HNF-6 and RORα.

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Ligand-inducible retinoid X receptor-mediated protein: DNA interactions in the retinoic acid receptor β2 gene promoter in vivo

Molecular and Cellular Endocrinology ◽

10.1016/s0303-7207(97)00217-7 ◽

1998 ◽

Vol 136 (2) ◽

pp. 109-118 ◽

Cited By ~ 1

Author(s):

Masato Ikeda ◽

Remco A Spanjaard ◽

Elizabeth W Noordhoek ◽

Akio Kawaguchi ◽

Toshimasa Onaya ◽

...

Keyword(s):

Retinoic Acid ◽

Retinoic Acid Receptor ◽

Gene Promoter ◽

Retinoid X Receptor ◽

Dna Interactions ◽

Acid Receptor ◽

Protein Dna Interactions ◽

Retinoic Acid Receptor Β2

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Cooperation of Cytokine Signaling with Chimeric Transcription Factors in Leukemogenesis: PML-Retinoic Acid Receptor Alpha Blocks Growth Factor-Mediated Differentiation

Molecular and Cellular Biology ◽

10.1128/mcb.23.13.4573-4585.2003 ◽

2003 ◽

Vol 23 (13) ◽

pp. 4573-4585 ◽

Cited By ~ 9

Author(s):

Vernon T. Phan ◽

David B. Shultz ◽

Bao-Tran H. Truong ◽

Timothy J. Blake ◽

Anna L. Brown ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Transcription Factors ◽

Retinoic Acid ◽

Myeloid Leukemia ◽

Retinoic Acid Receptor ◽

Promyelocytic Leukemia ◽

Cytokine Signaling ◽

Retinoic Acid Receptor Alpha ◽

Acid Receptor ◽

Acute Myeloid

ABSTRACT We utilized a mouse model of acute promyelocytic leukemia (APL) to investigate how aberrant activation of cytokine signaling pathways interacts with chimeric transcription factors to generate acute myeloid leukemia. Expression in mice of the APL-associated fusion, PML-RARA, initially has only modest effects on myelopoiesis. Whereas treatment of control animals with interleukin-3 (IL-3) resulted in expanded myelopoiesis without a block in differentiation, PML-RARA abrogated differentiation that normally characterizes the response to IL-3. Retroviral transduction of bone marrow with an IL-3-expressing retrovirus revealed that IL-3 and promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) combined to generate a lethal leukemia-like syndrome in <21 days. We also observed that a constitutively activated mutant IL-3 receptor, βcV449E, cooperated with PML-RARα in leukemogenesis, whereas a different activated mutant, βcI374N, did not. Analysis of additional mutations introduced into βcV449E showed that, although tyrosine phosphorylation of βc is necessary for cooperation, the Src homology 2 domain-containing transforming protein binding site is dispensable. Our results indicate that chimeric transcription factors can block the differentiative effects of growth factors. This combination can be potently leukemogenic, but the particular manner in which these types of mutations interact determines the ability of such combinations to generate acute myeloid leukemia.

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Expression of nuclear factor Y, subunit C (NFY-C), and retinoic acid receptor-related orphan receptor alpha (RORA) in colorectal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2010.28.15_suppl.e14085 ◽

2010 ◽

Vol 28 (15_suppl) ◽

pp. e14085-e14085

Author(s):

T. Makatsoris

Keyword(s):

Retinoic Acid ◽

Colorectal Adenocarcinoma ◽

Retinoic Acid Receptor ◽

Orphan Receptor ◽

Nuclear Factor ◽

Subunit C ◽

Acid Receptor ◽

Receptor Alpha ◽

Nuclear Factor Y

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Neonatal Maternal Separation Alters the Capacity of Adult Neural Precursor Cells to Differentiate into Neurons Via Methylation of Retinoic Acid Receptor Gene Promoter

Biological Psychiatry ◽

10.1016/j.biopsych.2014.07.008 ◽

2015 ◽

Vol 77 (4) ◽

pp. 335-344 ◽

Cited By ~ 33

Author(s):

Shuken Boku ◽

Hiroyuki Toda ◽

Shin Nakagawa ◽

Akiko Kato ◽

Takeshi Inoue ◽

...

Keyword(s):

Retinoic Acid ◽

Maternal Separation ◽

Retinoic Acid Receptor ◽

Receptor Gene ◽

Gene Promoter ◽

Precursor Cells ◽

Neural Precursor Cells ◽

Neural Precursor ◽

Acid Receptor ◽

Neonatal Maternal Separation

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Acyclic retinoid inhibits functional interaction of transcription factors Krüppel-like factor 5 and retinoic acid receptor-alpha

FEBS Letters ◽

10.1016/j.febslet.2008.04.040 ◽

2008 ◽

Vol 582 (12) ◽

pp. 1755-1760 ◽

Cited By ~ 10

Author(s):

Nanae Kada ◽

Toru Suzuki ◽

Kenichi Aizawa ◽

Yoshiko Munemasa ◽

Takayoshi Matsumura ◽

...

Keyword(s):

Transcription Factors ◽

Retinoic Acid ◽

Retinoic Acid Receptor ◽

Retinoic Acid Receptor Alpha ◽

Functional Interaction ◽

Acid Receptor ◽

Receptor Alpha ◽

Acyclic Retinoid

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Suppression of nephrin expression by TNF-α via interfering with the cAMP-retinoic acid receptor pathway

AJP Renal Physiology ◽

10.1152/ajprenal.00512.2009 ◽

2010 ◽

Vol 298 (6) ◽

pp. F1436-F1444 ◽

Cited By ~ 26

Author(s):

Yukinori Saito ◽

Maro Okamura ◽

Shotaro Nakajima ◽

Kunihiro Hayakawa ◽

Tao Huang ◽

...

Keyword(s):

Retinoic Acid ◽

Map Kinases ◽

Retinoic Acid Receptor ◽

Selective Inhibition ◽

Nuclear Factor Κb ◽

Suppressive Effect ◽

Glomerular Diseases ◽

Acid Receptor ◽

Dihydroxyvitamin D ◽

Tnf Α

Nephrin, a crucial component of the slit diaphragm, is downregulated in proteinuric glomerular diseases including glomerulonephritis. We previously reported that 1) expression of nephrin in cultured podocytes is reinforced by retinoic acid (RA) and 1,25-dihydroxyvitamin D3, 2) these effects are mediated by retinoic acid receptor (RAR) and vitamin D receptor (VDR), and 3) basal and inducible expression of nephrin is downregulated by TNF-α. In the present investigation, we identified that TNF-α selectively represses activity of RAR but not VDR. To elucidate mechanisms underlying this observation, we tested involvement of downstream targets for TNF-α: nuclear factor-κB (NF-κB), mitogen-activated protein (MAP) kinases, phosphatidylinositol 3-kinase (PI3K)-Akt, and cAMP-protein kinase A (PKA). TNF-α caused activation of NF-κB, MAP kinases, and PI3K-Akt in podocytes, whereas blockade of these molecules did not affect inhibition of RAR by TNF-α. In contrast, TNF-α depressed activity of cAMP-PKA, and blockade of PKA inhibited basal and RA-induced activation of RAR. Furthermore, activity of RAR was significantly upregulated by cAMP, and the suppressive effect of TNF-α on RAR was reversed by cAMP-elevating agents. These results suggest that 1) expression of nephrin in podocytes is regulated by the cAMP-RAR pathway and 2) suppression of nephrin by TNF-α is caused, at least in part, through selective inhibition of this pathway.

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