CREB is a critical regulator of normal hematopoiesis and leukemogenesis

Cheng, Jerry C.; Kinjo, Kozen; Judelson, Dejah R.; Chang, Jenny C.; Wu, Winston S.; Schmid, Ingrid; Shankar, Deepa B.; Kasahara, Noriyuki; Stripecke, Renata; Bhatia, Ravi; Landaw, Elliot M.; Sakamoto, Kathleen M.

doi:10.1182/blood-2007-04-083600

Cited by 93 publications

(128 citation statements)

References 44 publications

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“…Results demonstrated that CREB protein levels were high in HeLa and in all leukemia cell lines (Figure 1), but undetectable in sorted normal hematopoietic stem cells. On the contrary, ICER was not detected in any of the analyzed cell lines, but was expressed in normal hematopoietic cells (CD34À), supporting the association of CREB expression with leukemic tissue 19 and ICER with healthy tissue. The stable expression of ICER (HL60 þ ICER in Figure 1a), as well as the transient transfection of ICER (t ICER in Figure 1b) in HeLa and HL60 induced the reduction of the active phosphorylated form of CREB (P-CREB) compared with transfected controls (t EV).…”

Section: Icer Decreases Creb Expression In Hela and Hl60mentioning

confidence: 63%

ICER expression inhibits leukemia phenotype and controls tumor progression

et al. 2008

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The inducible cyclic AMP (cAMP) early repressor (ICER) and cAMP response element-binding protein (CREB) are transcriptional regulators of the cAMP-mediated signaling pathway. CREB has been demonstrated to be upregulated in the majority of childhood leukemias contributing to disease progression, whereas ICER, its endogenous repressor, was found to be downregulated. Our research focus has been the function of restored ICER expression. ICER exogenously expressed in cell lines decreases CREB protein level and induces a lowered clonogenic potential in vitro. It decreases the ability of HL60 to invade the extramedullary sites and to promote bone marrow angiogenesis in nonobese diabetic-severe combined immunodeficient mice, demonstrating its potential effects on tumor progression. ICER represses the majority of 96 target genes upregulated by CREB. It binds CRE promoters and controls gene expression restoring the normal regulation of major cellular pathways. ICER is subjected to degradation through a constitutively active form of the extracellular signal-regulated protein kinase, which drives it to the proteasome. We propose that ICER is downregulated in HL60 to preserve CREB overexpression, which disrupts normal myelopoiesis and promotes blast proliferation. These findings define the function of ICER as a tumor suppressor in leukemia. Unbalanced CREB/ICER expression needs to be considered a pathogenetic feature in leukemogenesis. The molecular characterization of this pathway could be useful for novel therapeutic strategies.

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Section: Icer Decreases Creb Expression In Hela and Hl60mentioning

confidence: 63%

ICER expression inhibits leukemia phenotype and controls tumor progression

et al. 2008

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“…Krüppel-like factor family members have been implicated in ES cell self-renewal, and Klf4 is one of the four transcription factors required to reverse the highly differentiated state of somatic cells back to pluripotency (17,38). Creb1/CREB1 has been demonstrated to be a critical regulator of both normal hematopoiesis and leukemogenesis (5,36). We propose that Cbp may further regulate the function of these networks at a subset of loci through acetylation of histone and nonhistone proteins , these critical cell fate decisions are altered, leading to an increase in quiescence and apoptosis, to preferential differentiation, and ultimately HSC exhaustion through decreased self-renewal (red arrows).…”

Section: Discussionmentioning

confidence: 99%

The Transcriptional Coactivator Cbp Regulates Self-Renewal and Differentiation in Adult Hematopoietic Stem Cells

Chan

Hannah

Dawson

et al. 2011

Molecular and Cellular Biology

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The transcriptional coactivator Cbp plays an important role in a wide range of cellular processes, including proliferation, differentiation, and apoptosis. Although studies have shown its requirement for hematopoietic stem cell (HSC) development, its role in adult HSC maintenance, as well as the cellular and molecular mechanisms underlying Cbp function, is not clear. Here, we demonstrate a gradual loss of phenotypic HSCs and differentiation defects following conditional ablation of Cbp during adult homeostasis. In addition, Cbp-deficient HSCs reconstituted hematopoiesis with lower efficiency than their wild-type counterparts, and this response was readily exhausted under replicative stress. This phenotype relates to an alteration in cellular fate decisions for HSCs, with Cbp loss leading to an increase in differentiation, quiescence, and apoptosis. Genome-wide analyses of Cbp occupancy and differential gene expression upon Cbp deletion identified HSCspecific genes regulated by Cbp, providing a molecular basis for the phenotype. Finally, Cbp binding significantly overlapped at genes combinatorially bound by 7 major hematopoietic transcriptional regulators, linking Cbp to a critical HSC transcriptional regulatory network. Our data demonstrate that Cbp plays a role in adult HSC homeostasis by maintaining the balance between different HSC fate decisions, and our findings identify a putative HSC-specific transcriptional network coordinated by Cbp.

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“…Thus, CREB controls critical cellular processes and is involved in the regulation of immortalization and malignant transformation (11). Recently, CREB was found to be overexpressed in many solid tumors of distinct histology when compared with normal adjacent tissues (12)(13)(14) and hematologic malignancies (3,15,16), which could be linked in some cases to tumor progression (14,17), decreased time to relapse, and decreased event-free survival of patients (18). On the basis of the important role of tumor progression, CREB represents a promising target for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

“…In order to gain novel insights into the role of CREB activation in the malignant phenotype, in vitro models of ras-transformed cells represent suitable tools for such analyses. Because K-ras genes are often mutated in tumors of distinct histology, which is frequently associated with a poor prognosis and worse clinical outcome of patients (25,26) as well as resistance to targeted therapies (15,27), it was analyzed whether CREB contributes to the K-RAS V12 -transformed phenotype of murine fibroblasts and human K-RAS V12 -mutated colorectal carcinoma cell lines and lesions.…”

Section: Introductionmentioning

confidence: 99%

Colorectal Carcinogenesis: Connecting K-RAS–Induced Transformation and CREB Activity In Vitro and In Vivo

Steven

Heiduk

Recktenwald

et al. 2015

Molecular Cancer Research

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Oncogenic transformation is often associated with an increased expression of the cAMP response element binding (CREB) transcription factor controlling the expression of genes involved in cell proliferation, cell cycle, apoptosis, and tumor development, but a link between K-RAS V12 -induced transformation and CREB has not yet been determined. Therefore, the constitutive and/or inhibitor-regulated mRNA and protein expression of CREB and signal transduction components and growth properties of parental fibroblasts, K-RAS V12 -transformed counterparts, shCREB K-RAS V12 transfectants and human colon carcinoma cells were determined. Increased CREB transcript and protein levels accompanied by an enhanced CREB activity was detected in K-RAS V12 -transformed murine fibroblasts and K-RAS V12 -mutated human tumor cells, which is dependent on the MAPK/MEK, PI3K, and/or PKC signal transduction. Immunohistochemical (IHC) staining of colorectal carcinoma lesions and murine tumors, with known KRAS gene mutation status, using antibodies specific for CREB and phospho-CREB, revealed a mechanistic link between CREB expression and K-RAS V12 -mutated colorectal carcinoma lesions when compared with control tissues. Silencing of CREB by shRNA and/or treatment with a CREB inhibitor (KG-501) reverted the neoplastic phenotype of K-RAS V12 transformants as demonstrated by a more fibroblast-like morphology, enhanced apoptosis sensitivity, increased doubling time, decreased migration, invasion and anchorage-independent growth, reduced tumorigenesis, and enhanced immunogenicity in vivo. The impaired shCREB-mediated invasion of K-RAS V12 transformants was accompanied by a transcriptional downregulation of different matrix metalloproteinases (MMP) coupled with their reduced enzymatic activity.Implications: CREB plays a key role in the K-RAS V12

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CREB is a critical regulator of normal hematopoiesis and leukemogenesis

Cited by 93 publications

References 44 publications

ICER expression inhibits leukemia phenotype and controls tumor progression

ICER expression inhibits leukemia phenotype and controls tumor progression

The Transcriptional Coactivator Cbp Regulates Self-Renewal and Differentiation in Adult Hematopoietic Stem Cells

Colorectal Carcinogenesis: Connecting K-RAS–Induced Transformation and CREB Activity In Vitro and In Vivo

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