A transcription factor party during blood cell differentiation

Sieweke, Michael H.; Graf, Thomas

doi:10.1016/s0959-437x(98)80009-9

Cited by 153 publications

(98 citation statements)

References 58 publications

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“…In our view, multiple enhancer binding proteins need to be available simultaneously in differentiated monocytes to achieve stable binding site occupancy required for maximally activated IL-10 transcription. This suggestion is in agreement with the observation that C/EBP␣ expression is tissue-specific and varies during differentiation, while CREB/ATF is ubiquitously expressed (35,36). Therefore, C/EBP-mediated transcription of a gene, in particular IL-10, is regulated in a tissue-specific manner and depends on the state of differentiation of a given cell.…”

Section: Camp-induced Il-10 Promoter Activationsupporting

confidence: 91%

cAMP-induced Interleukin-10 Promoter Activation Depends on CCAAT/Enhancer-binding Protein Expression and Monocytic Differentiation

Brenner

Prösch

Schenke‐Layland

et al. 2003

Journal of Biological Chemistry

137

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Section: Camp-induced Il-10 Promoter Activationsupporting

confidence: 91%

cAMP-induced Interleukin-10 Promoter Activation Depends on CCAAT/Enhancer-binding Protein Expression and Monocytic Differentiation

Brenner

Prösch

Schenke‐Layland

et al. 2003

Journal of Biological Chemistry

137

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“…58 Since the c-kit and SCL genes are transcribed in early progenitors and are progressively extinguished as differentiation proceeds, our study places SCL among the first regulators in the hierarchy of transcription factor complexes that shape hematopoiesis. We have previously shown that SCL genetically interacts with E2A to prevent commitment into the B lineage.…”

Section: Diversification Through Protein-protein Interactionmentioning

confidence: 86%

The SCL complex regulates c-kit expression in hematopoietic cells through functional interaction with Sp1

Lécuyer

Herblot²,

Saint-Denis³

et al. 2002

Blood

153

188

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The combinatorial interaction among transcription factors is believed to determine hematopoietic cell fate. Stem cell leukemia (SCL, also known as TAL1 [T-cell acute lymphoblastic leukemia 1]) is a tissue-specific basic helix-loop-helix (bHLH) factor that plays a central function in hematopoietic development; however, its target genes and molecular mode of action remain to be elucidated. Here we show that SCL and the c-Kit receptor are coexpressed in hematopoietic progenitors at the single-cell level and that SCL induces c-kit in chromatin, as ectopic SCL expression in transgenic mice sustains c-kit transcription in developing B lymphocytes, in which both genes are normally down-regulated. Through transient transfection assays and coimmunoprecipitation of endogenous proteins, we define the role of SCL as a nucleation factor for a multifactorial complex (SCL complex) that specifically enhances c-kit promoter activity without affecting the activity of myelomonocytic promoters. This complex, containing hematopoieticspecific (SCL, Lim-only 2 (LMO2), GATA-1/ GATA-2) and ubiquitous (E2A, LIMdomain binding protein 1 [Ldb-1]) factors, is tethered to DNA via a specificity protein 1 (Sp1) motif, through direct interactions between elements of the SCL complex and the Sp1 zinc finger protein. Furthermore, we demonstrate by chromatin immunoprecipitation that SCL, E2A, and Sp1 specifically co-occupy the c-kit promoter in vivo. We therefore conclude that c-kit is a direct target of the SCL complex. Proper activation of the c-kit promoter depends on the combinatorial interaction of all members of the complex. Since SCL is down-regulated in maturing cells while its partners remain expressed, our observations suggest that loss of SCL inactivates the SCL complex, which may be an important event in the differentiation of pluripotent hematopoietic cells. Tissue-restricted members can regulate gene expression by binding to E-box DNA sequences (CANNTG) following heterodimerization with ubiquitously expressed E2A gene products (E12 and E47) or HEB. Different dimers exhibit preferential binding to specific E-boxes, and this selectivity is thought to be an important determinant in the spatio-temporal control of gene expression. SCL is a prototypic tissue-specific bHLH factor normally expressed in pluripotent hematopoietic precursors, vascular endothelial cells, and the central nervous system (reviewed in Begley and Green 2 ) and acts as a master regulator of hematopoietic development. Indeed, SCL Ϫ/Ϫ mice lack all primitive and definitive hematopoietic lineages and precursors. 3,4 Complementary-gain-of-function experiments in zebra fish and Xenopus have demonstrated that SCL plays a role in specifying the formation of hemangioblasts, the common precursors of vascular endothelial and hematopoietic stem cells. [5][6][7] As for many hematopoietic transcription regulators, the SCL gene was originally identified by virtue of its involvement in a tumor-specific translocation. 2 In fact, chromosomal rearrangements causing aberrant activation of...

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“…Modified properties of a multiprotein complex resulting from variable interacting partners are likely to be involved with all three hematopoietic checkpoints: cell proliferation, differentiation and apoptosis; impairment of each of which may induce leukemia. Hence, an important emerging concept is that not only relative expression of transcription factors is important, but that protein-protein interactions among various transcription factors are crucial (Sieweke and Graf, 1998). Potential antagonistic protein interactions leading to a block in C/EBPa function in AML have been well implicated in recent findings (Pabst et al, 2001a;Vangala et al, 2003;Zheng et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Proteomic identification of C/EBP-DBD multiprotein complex: JNK1 activates stem cell regulator C/EBPα by inhibiting its ubiquitination

et al. 2006

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Functional inactivation of transcription factors in hematopoietic stem cell development is involved in the pathogenesis of acute myeloid leukemia (AML). Stem cell regulator C/enhancer binding protein (EBP)a is among such transcription factors known to be inactive in AML. This is either due to mutations or inhibition by protein-protein interactions. Here, we applied a mass spectrometry-based proteomic approach to systematically identify putative co-activator proteins interacting with the DNA-binding domain (DBD) of C/EBP transcription factors. In our proteomic screen, we identified c-Jun N-terminal kinase (JNK) 1 among others such as PAK6, MADP-1, calmodulin-like skin proteins and ZNF45 as proteins interacting with DBD of C/EBPs from nuclear extract of myelomonocytic U937 cells. We show that kinase JNK1 physically interacts with DBD of C/EBPa in vitro and in vivo. Furthermore, we show that active JNK1 inhibits ubiquitination of C/EBPa possibly by phosphorylating in its DBD. Consequently, JNK1 prolongs C/EBPa protein half-life leading to its enhanced transactivation and DNA-binding capacity. In certain AML patients, however, the JNK1 mRNA expression and its kinase activity is decreased which suggests a possible reason for C/EBPa inactivation in AML. Thus, we report the first proteomic screen of C/EBP-interacting proteins, which identifies JNK1 as positive regulator of C/EBPa.

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A transcription factor party during blood cell differentiation

Cited by 153 publications

References 58 publications

cAMP-induced Interleukin-10 Promoter Activation Depends on CCAAT/Enhancer-binding Protein Expression and Monocytic Differentiation

cAMP-induced Interleukin-10 Promoter Activation Depends on CCAAT/Enhancer-binding Protein Expression and Monocytic Differentiation

The SCL complex regulates c-kit expression in hematopoietic cells through functional interaction with Sp1

Proteomic identification of C/EBP-DBD multiprotein complex: JNK1 activates stem cell regulator C/EBPα by inhibiting its ubiquitination

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