The Role of Heterodimeric AP-1 Protein Comprised of JunD and c-Fos Proteins in Hematopoiesis

Lee, Sung Young; Yoon, Jaeho; Lee, Mee-Hyun; Jung, Sung Keun; Kim, Dong Joon; Bode, Ann M.; Kim, Jaebong; Dong, Zigang

doi:10.1074/jbc.m112.387266

Cited by 28 publications

(24 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regulation of CYP2C9 by AP-1 Activation and DNA Looping However, Dong and coworkers provided evidence that hematopoietic genes were induced by a transcriptionally active heterodimer of cFos and JunD (Lee et al, 2012). Ectopic expression of Nrf2 had no significant effect on CYP2C9-promoter luciferase activity alone or in combination with cJun.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Human CYP2C9 Expression by Electrophilic Stress Involves Activator Protein 1 Activation and DNA Looping

et al. 2014

View full text Add to dashboard Cite

Cytochrome P450 (CYP)2C9 and CYP2C19 are important human enzymes that metabolize therapeutic drugs, environmental chemicals, and physiologically important endogenous compounds. Initial studies using primary human hepatocytes showed induction of both the CYP2C9 and CYP2C19 genes by tertbutylhydroquinone (tBHQ). As a pro-oxidant, tBHQ regulates the expression of cytoprotective genes by activation of redox-sensing transcription factors, such as the nuclear factor E2-related factor 2 (Nrf2) and members of the activator protein 1 (AP-1) family of proteins. The promoter region of CYP2C9 contains two putative AP-1 sites (TGAGTCA) at positions 22201 and 21930, which are also highly conserved in CYP2C19. The CYP2C9 promoter is activated by ectopic expression of cFos and JunD, whereas Nrf2 had no effect. Using specific kinase inhibitors for mitogen-activated protein kinase, we showed that extracellular signal-regulated kinase and Jun N-terminal kinase are essential for tBHQinduced expression of CYP2C9. Electrophoretic mobility shift assays demonstrate that cFos distinctly interacts with the distal AP-1 site and JunD with the proximal site. Because cFos regulates target genes as heterodimers with Jun proteins, we hypothesized that DNA looping might be required to bring the distal and proximal AP-1 sites together to activate the CYP2C9 promoter. Chromosome conformation capture analyses confirmed the formation of a DNA loop in the CYP2C9 promoter, possibly allowing interaction between cFos at the distal site and JunD at the proximal site to activate CYP2C9 transcription in response to electrophiles. These results indicate that oxidative stress generated by exposure to electrophilic xenobiotics and metabolites induces the expression of CYP2C9 and CYP2C19 in human hepatocytes.

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of Human CYP2C9 Expression by Electrophilic Stress Involves Activator Protein 1 Activation and DNA Looping

et al. 2014

View full text Add to dashboard Cite

show abstract

“…While JUN family proteins can dimerize with FOS, JUN, ATF and JDP proteins, FOS family proteins can heterodimerize with only JUN family members. Several findings point to an important role of this TF family at early stages of hematopoietic specification: (1) work from our group found that AP-1 motifs were enriched in open chromatin regions and colocalized with TF-binding sites that were specific to HE cells differentiated from mouse embryonic stem cells (ESCs) (Goode et al, 2016; Lichtinger et al, 2012); (2) JUN knockout (KO) mice die around the onset of HSC emergence (Eferl et al, 1999); (3) AP-1 was reported to play a role in Xenopus hematopoiesis (Lee et al, 2012); (4) in zebrafish, the transcriptional co-repressor NCoR silences Fos transcription and NCoR knockdown leads to inhibition of HE formation (Wei et al, 2014); (5) AP-1 activation is involved in the stimulation of engraftment of HSCs by epoxyeicosatrienonic acids (Li et al, 2015); and (6) FOS has been identified as a crucial factor together with GATA2, GFI1B and ETV6, in the reprogramming of mouse embryonic fibroblasts (MEFs) to blood cells (Pereira et al, 2013). However, none of these studies has identified the global genomic targets responsible for these effects.…”

Section: Introductionmentioning

confidence: 99%

Cooperative binding of AP-1 and TEAD4 modulates the balance between vascular smooth muscle and hemogenic cell fate

et al. 2016

View full text Add to dashboard Cite

The transmission of extracellular signals into the nucleus involves inducible transcription factors, but how different signalling pathways act in a cell type-specific fashion is poorly understood. Here, we studied the regulatory role of the AP-1 transcription factor family in blood development using embryonic stem cell differentiation coupled with genome-wide transcription factor binding and gene expression analyses. AP-1 factors respond to MAP kinase signalling and comprise dimers of FOS, ATF and JUN proteins. To examine genes regulated by AP-1 and to examine how it interacts with other inducible transcription factors, we abrogated its global DNA-binding activity using a dominant-negative FOS peptide. We show that FOS and JUN bind to and activate a specific set of vascular genes and that AP-1 inhibition shifts the balance between smooth muscle and hematopoietic differentiation towards blood. Furthermore, AP-1 is required for de novo binding of TEAD4, a transcription factor connected to Hippo signalling. Our bottom-up approach demonstrates that AP-1- and TEAD4-associated cis-regulatory elements form hubs for multiple signalling-responsive transcription factors and define the cistrome that regulates vascular and hematopoietic development by extrinsic signals.

show abstract

“…In addition, AP-1 c-Jun/c-Fos regulates Zic3 expression when stimulated with activin (Lee et al, 2004). Under normal circumstances, AP-1 JunD/c-Fos functions in BMP signaling during hematopoiesis (Lee et al, 2012). In the present work, we elucidated the role of AP-1 c-Jun/ FosB in DNBR-induced FoxD5b expression.…”

Section: Fig 4 An Ap-1 Complex Composed Of C-jun and Fosb Induced Fmentioning

confidence: 57%

AP-1^c-Jun/FosBmediates xFoxD5b expression in Xenopus early developmental neurogenesis

et al. 2013

Self Cite

View full text Add to dashboard Cite

The Role of Heterodimeric AP-1 Protein Comprised of JunD and c-Fos Proteins in Hematopoiesis

Cited by 28 publications

References 29 publications

Regulation of Human CYP2C9 Expression by Electrophilic Stress Involves Activator Protein 1 Activation and DNA Looping

Regulation of Human CYP2C9 Expression by Electrophilic Stress Involves Activator Protein 1 Activation and DNA Looping

Cooperative binding of AP-1 and TEAD4 modulates the balance between vascular smooth muscle and hemogenic cell fate

AP-1^c-Jun/FosBmediates xFoxD5b expression in Xenopus early developmental neurogenesis

Contact Info

Product

Resources

About

The Role of Heterodimeric AP-1 Protein Comprised of JunD and c-Fos Proteins in Hematopoiesis

Cited by 28 publications

References 29 publications

Regulation of Human CYP2C9 Expression by Electrophilic Stress Involves Activator Protein 1 Activation and DNA Looping

Regulation of Human CYP2C9 Expression by Electrophilic Stress Involves Activator Protein 1 Activation and DNA Looping

Cooperative binding of AP-1 and TEAD4 modulates the balance between vascular smooth muscle and hemogenic cell fate

AP-1c-Jun/FosBmediates xFoxD5b expression in Xenopus early developmental neurogenesis

Contact Info

Product

Resources

About

AP-1^c-Jun/FosBmediates xFoxD5b expression in Xenopus early developmental neurogenesis