Regulation of Steroidogenesis and the Steroidogenic Acute Regulatory Protein by a Member of the cAMP Response-Element Binding Protein Family

Manna, Pulak R.

doi:10.1210/me.16.1.184

Cited by 74 publications

(132 citation statements)

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“…The evidence that ICER acts as a tumor suppressor gene in leukemia cell line HL60, as reported previously for other solid tumors, [28][29][30] first comes from the decreased clonogenicity ability of HL60 þ ICER cells in vitro. We used immunodeficent mice to confirm these data and reveal that HL60 þ ICER-injected mice have a mild leukemia phenotype for the reduced dissemination of tumor in extramedullary sites.…”

Section: Discussionsupporting

confidence: 68%

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: Discussionsupporting

confidence: 68%

ICER expression inhibits leukemia phenotype and controls tumor progression

et al. 2008

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“…The 5 0 -flanking -966/-1 bp region of the mouse StAR gene (in relation to the transcription start site) was cloned into the pGL3 basic vector (Promega), upstream of a luciferase reporter gene, utilizing the XhoI and HindIII sites (Manna et al 2002b. The identity of the inserted fragment was tested by restriction endonuclease digestion and by automated sequencing with a Perkin-Elmer Biosystem 310 Genetic Analyzer (ABI PRISM 310; Perkin-Elmer, Norwalk, CT, USA).…”

Section: Plasmids Transfections and Reporter Assaysmentioning

confidence: 99%

“…The identity of the inserted fragment was tested by restriction endonuclease digestion and by automated sequencing with a Perkin-Elmer Biosystem 310 Genetic Analyzer (ABI PRISM 310; Perkin-Elmer, Norwalk, CT, USA). Expression plasmids for wild-type CREB (WT-CREB) and non-phosphorylatable CREB (CREB-M1, Ser 133-Ala) have been previously described (Manna et al 2002b). The plasmid (pRL-SV40) containing the Renilla luciferase gene driven by the SV40 promoter (Promega) was used to normalize the transfection efficiency.…”

Section: Plasmids Transfections and Reporter Assaysmentioning

confidence: 99%

“…These studies demonstrated that the protein kinase C (PKC) signaling plays an important role in regulating StAR expression and steroidogenesis (Pilon et al 2003, as has the mitogen-activated protein kinase (MAPK) family of Ser-Thr kinases (Gyles et al 2001, Seger et al 2001, Manna et al 2002a, Martinelle et al 2004, Martinat et al 2005. In addition, StAR's transcriptional regulation has been shown to be mediated by several transcription factors, including the cAMP-response element-binding protein (CREB) and dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 (DAX-1) (Manna et al 2002b, 2006, Clem et al 2005. In addition, the scavenger receptor class B type 1 (SR-B1), a high-density lipoprotein receptor, was shown to be involved in regulating steroidogenesis by facilitating the mobilization of precursor cholesterol into steroidogenic cells (Rao et al 2003, Manna et al 2006.…”

Section: Introductionmentioning

confidence: 99%

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cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation

Manna¹,

Chandrala²,

Jo³

et al. 2006

Journal of Molecular Endocrinology

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In the regulation of steroid biosynthesis, a process mediated by the steroidogenic acute regulatory (StAR) protein, both cAMP-dependent and -independent pathways are involved. While the cAMP-dependent regulatory events represent, by far, the most robust increase in steroid synthesis and are well established, the knowledge regarding cAMP-independent mechanisms is lacking. The present investigation was designed to elucidate the potential involvement of the latter in regulating StAR expression and steroidogenesis in mouse Leydig tumor cells (mLTC-1 cells). Treatment of mLTC-1 cells with a number of factors including insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF), fibroblast growth factor, transforming growth factor (TGF)a, interleukin-1 (IL-1), and colony-stimulating factor-1, increased the levels of StAR mRNA, StAR protein, and progesterone to varying degrees and utilized signaling pathways that are not associated with elevations in intracellular cAMP levels. Importantly, phosphorylation of StAR in response to these stimuli was undetectable, which is in marked contrast to observations with human chorionic gonadotropin (hCG), indicating factors that do not alter intracellular cAMP, regulate the steroid biosynthesis in a StAR phosphorylation-independent manner. In addition, the roles for factors involved in cross-talk between the protein kinase pathways, PKA and PKC, were demonstrated. Further characterization of signaling by one such cAMP-independent factor, TGFa, demonstrated that the mechanism, whereby it increased StAR expression and steroid synthesis, was dependent on de novo protein synthesis and mediated via activation of the EGF receptor. TGFa was also able to augment hCG-stimulated cAMP synthesis, StAR protein and StAR phosphorylation, and influence hCG binding and LH receptor mRNA expression. Furthermore, TGFa increased phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and cAMP-response element-binding protein (CREB), processes inhibited by the mitogen-activated protein kinase/ERK inhibitor U0126 and by expression of non-phosphorylatable CREB-M1 respectively. Inhibition of ERK activity enhanced TGFa-mediated StAR protein expression (but not its phosphorylation) and decreased progesterone synthesis, events correlated with the expression of dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 (DAX-1) and scavenger receptor class B type 1 (SR-B1). Collectively, these findings demonstrate that, in mouse Leydig cells, cAMPindependent signaling events regulate steroidogenesis in a StAR phosphorylation-independent manner.

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“…NR4A orphan receptors are transcription factors that belong to the superfamily of steroid nuclear hormone receptors that have been associated with different cellular processes, including inflammation (Murphy et al 2001;Pei et al 2005), steroidogenesis (Manna et al 2002), apoptosis (Winoto and Littman 2002), development of dopaminergic Concise summary Non-selective AR engagement triggers robust induction NR4A orphan receptors in mast cells. Induction of these early responsive genes can be blocked by selective activation of the anti-inflammatory A 2A AR not only in the context of adenosine but also of PMA signaling, suggesting a general mechanism of mast cell regulation.…”

Section: Introductionmentioning

confidence: 99%

Selective regulation of nuclear orphan receptors 4A by adenosine receptor subtypes in human mast cells

Zhang

Paine

Dip

2010

J. Cell Commun. Signal.

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Nuclear orphan receptors 4A (NR4A) are early responsive genes that belong to the superfamily of hormone receptors and comprise NR4A1, NR4A2 and NR4A3. They have been associated to transcriptional activation of multiple genes involved in inflammation, apoptosis and cell cycle control. Here, we establish a link between NR4As and adenosine, a paradoxical inflammatory molecule that can contribute to persistence of inflammation or mediate inflammatory shutdown. Transcriptomics screening of the human mast cell-line HMC-1 revealed a sharp induction of transcriptionally active NR4A2 and NR4A3 by the adenosine analogue NECA. The concomitant treatment of NECA and the adenosine receptor A 2A (A 2A AR) selective antagonist SCH-58261 exaggerated this effect, suggesting that upregulation of these factors in mast cells is mediated by other AR subtypes (A 2B and A 3 ) and that A 2A AR activation counteracts NR4A2 and NR4A3 induction. In agreement with this, A 2A ARsilencing amplified NR4A induction by NECA. Interestingly, a similar A 2A AR modulatory effect was observed on ERK1/2 phosphorylation because A 2A AR blockage exacerbated NECA-mediated phosphorylation of ERK1/2. In addition, PKC or MEK1/2 inhibition prevented ERK1/2 phosphorylation and antagonized AR-mediated induction of NR4A2 and NR4A3, suggesting the involvement of these kinases in AR to NR4A signaling. Finally, we observed that selective A 2A AR activation with CGS-21680 blocked PMA-induced ERK1/2 phosphorylation and modulated the overexpression of functional nuclear orphan receptors 4A. Taken together, these results establish a novel PKC/ERK/nuclear orphan receptors 4A axis for adenosinergic signaling in mast cells, which can be modulated by A 2A AR activation, not only in the context of adenosine but of other mast cell activating stimuli as well.

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Regulation of Steroidogenesis and the Steroidogenic Acute Regulatory Protein by a Member of the cAMP Response-Element Binding Protein Family

Cited by 74 publications

References 0 publications

ICER expression inhibits leukemia phenotype and controls tumor progression

ICER expression inhibits leukemia phenotype and controls tumor progression

cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation

Selective regulation of nuclear orphan receptors 4A by adenosine receptor subtypes in human mast cells

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