ICER-IIγ is a tumor suppressor that mediates the antiproliferative activity of cAMP

Razavi, Reza; Ramos, Juan Carlos; Yehia, Ghassan; Schlotter, Florence; Molina, Carlos A.

doi:10.1038/sj.onc.1202225

Cited by 31 publications

(28 citation statements)

References 11 publications

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“…CREM repressors regulate CCND2 by binding this CRE (24). Repressor isoforms of CREM share the DNA binding and dimerization domains of CREM activators but lack kinase and trans-activation domains and therefore act as potent dominant negative transcription inhibitors (30)(31)(32). CREM repressor activity is regulated by gene expression rather than by posttranslational modification (32,33).…”

Section: Discussionmentioning

confidence: 99%

Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity

Tiedemann¹,

Mao²,

Shi³

et al. 2008

J. Clin. Invest.

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Knockout and transgenic studies in mice demonstrate that normal somatic tissues redundantly express 3 cyclin D proteins, whereas tumor cells seem dependent on a single overexpressed cyclin D. Thus, selective suppression of the individual cyclin D deregulated in a tumor represents a biologically valid approach to targeted cancer therapy. In multiple myeloma, overexpression of 1 of the cyclin D proteins is a ubiquitous feature, unifying at least 7 different initiating genetic events. We demonstrate here that RNAi of genes encoding cyclin D1 and cyclin D2 (CCND1 and CCND2, respectively) inhibits proliferation and is progressively cytotoxic in human myeloma cells. By screening a chemical library using a cell-based assay for inhibition of CCND2 trans-activation, we identified the plant cytokinin kinetin riboside as an inhibitor of CCND2 trans-activation. Kinetin riboside induced marked suppression of CCND2 transcription and rapidly suppressed cyclin D1 and D2 protein expression in primary myeloma cells and tumor lines, causing cell-cycle arrest, tumor cell-selective apoptosis, and inhibition of myeloma growth in xenografted mice. Mechanistically, kinetin riboside upregulated expression of transcription repressor isoforms of cAMP-response element modulator (CREM) and blocked both trans-activation of CCND2 by various myeloma oncogenes and cis-activation of translocated CCND1, suggesting induction of an overriding repressor activity that blocks multiple oncogenic pathways targeting cyclin D genes. These data support targeted repression of cyclin D genes as a therapeutic strategy for human malignancies. IntroductionMultiple myeloma (MM) is a postgerminal center B cell malignancy characterized by clonal plasma cell expansion. The disease manifests clinically with anemia, monoclonal immunoglobulin, renal insufficiency, and lytic bone lesions and currently affects 63,000 people in the United States alone (1); moreover, as it is currently incurable, MM causes a disproportionate 2% of all cancer deaths.Although myeloma tumors present with complex karyotypes and an assortment of structural and numerical chromosomal abnormalities, these tumors are unified in their ubiquitous targeting of cyclin D genes for overexpression. Of MM tumors, 54% overexpress cyclin D1 (CCND1), 48% overexpress cyclin D2 (CCND2), 3% overexpress cyclin D3 (CCND3), and 8% overexpress both CCND1 and CCND2 (2). Deregulated expression of single CCND genes in MM occurs as the result of selective cyclin D gene trans-activation by deregulated transcription factors or from translocation of a single

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Section: Discussionmentioning

confidence: 99%

Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity

Tiedemann¹,

Mao²,

Shi³

et al. 2008

J. Clin. Invest.

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“…For example, PPT-I is overexpressed in breast and other endocrine cancers, and the high levels of PPT-I peptides appear to be involved in autocrine proliferation of the cancer cells (4). In fact, overexpression of the inducible repressor, ICERII␥, in endocrine and neuroendocrine cancers alters the growth of these tumors (30). Also, PKA, a cAMP-dependent kinase, is implicated in different types of cancer (31)(32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Cloning of Human Preprotachykinin-I Promoter and the Role of Cyclic Adenosine 5′-Monophosphate Response Elements in Its Expression by IL-1 and Stem Cell Factor

Qian¹,

Yehia

Molina

et al. 2001

The Journal of Immunology

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Preprotachykinin-I gene (PPT-I) encodes several peptides with organ-specific functions that link the neuroendocrine-immune-hemopoietic axis. We cloned upstream of the initiation site of human PPT-I promoter and identified consensus sequences for two cAMP response elements (CRE). PPT-I is induced by cytokines including those that signal through the cAMP pathway. Therefore, we studied the role of the two CRE in IL-1α and stem cell factor (SCF) stimulation of bone marrow stroma because both cytokines induce endogenous PPT-I in these cells and activate the cAMP pathway. Furthermore, bone marrow stroma expresses the transcription factors regulated by the cAMP pathways such as the repressor (ICERIIγ) and activator (CREMτ). Mutagenesis of the two CRE and/or cotransfection with vectors that express ICERIIγ or CREMτ indicated that the two CRE have major roles in PPT-I expression. The two CRE are also required for optimal promoter activity by SCF and IL-1α. A particular cytokine could concomitantly induce PPT-I and the high affinity G protein-coupled receptor for PPT-I peptides, NK-1R. We showed that SCF, a representative cytokine, induced PPT-I and NK-1R leading to autocrine and/or paracrine cell activation. Because NK-1R activates cAMP through the G protein, the results suggest that the presence of CRE sequences within PPT-I promoter could be important in the regulation of PPT-I expression by cytokines, irrespective of their ability to signal through cAMP. As PPT-I is implicated in hemopoietic regulation, immune responses, breast cancer, and other neural functions, these studies add to the basic biology of these processes and could provide targets for drug development.

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“…This negative feedback control of ICER transcription is physiologically important for correct cAMPdependent gene expression in different tissues. 2 ICER activity is determined by its intracellular levels rather than by posttranslational modification, as it lacks the phosphorylation domain (P-box) typical of its CREB/CREM family member proteins. ICER expression depends on CREB/ICER transcriptional activity and its protein degradation rate.…”

Section: Introductionmentioning

confidence: 99%

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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ICER-IIγ is a tumor suppressor that mediates the antiproliferative activity of cAMP

Cited by 31 publications

References 11 publications

Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity

Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity

Cloning of Human Preprotachykinin-I Promoter and the Role of Cyclic Adenosine 5′-Monophosphate Response Elements in Its Expression by IL-1 and Stem Cell Factor

ICER expression inhibits leukemia phenotype and controls tumor progression

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