Metabolic Regulation of Gene Transcription ,

Gurney, Austin; Park, Edwards A.; Liu, Jinsong; Giralt, Marta; McGrane, Mary M.; Patel, Yashomita M.; Crawford, Deborah R.; Nizielski, Steven E.; Savon, Summer; Hanson, Richard W.

doi:10.1093/jn/124.suppl_8.1533s

Cited by 29 publications

(26 citation statements)

References 39 publications

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“…Opposing actions of Jun and Fos have already been reported for the phosphoenolpyruvate carboxykinase gene promoter (Gurney et al, 1992). Yet, one can mention that in co-transfection experiments, the negative e ect of PKCa on the activity of the Cdx-2 promoter is lower than the action exerted by Ha-ras.…”

Section: Discussionmentioning

confidence: 80%

Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras

et al. 1999

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Constitutive activation of the ras proto-oncogene is a frequent and early event in colon cancers, but the downstream nuclear targets are not fully understood. The Cdx-1 and Cdx-2 homeobox genes play crucial roles in intestinal cell proliferation and di erentiation. In addition, Cdx-2 is a colonic tumour-suppressor gene, whereas Cdx-1 has oncogenic potential. Here, we show that constitutive activation of ras alters Cdx-1 and Cdx-2 expression in human colonic Caco-2 and HT-29 cells that harbour a normal ras proto-oncogene. Oncogenic ras downregulates Cdx-2 through activation of the PKC pathway and a decline in activity of the Cdx-2 promoter AP-1 site. This decline results from a PKC-dependent decrease in the relative expression of c-Jun, an activator of Cdx-2 transcription, compared to c-Fos, an inhibitor of Cdx-2. Unlike Cdx-2, Cdx-1 is upregulated by oncogenic ras and this e ect is mediated by activation of the MEK1 pathway. These results indicate that oncogenic ras activation has opposite e ects on Cdx-1 and Cdx-2 expression through distinct signalling pathways and they provide the ®rst evidence for a functional link between ras activation and the downregulation of the Cdx-2 tumour-suppressor gene in colon cancer cells.

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Section: Discussionmentioning

confidence: 80%

Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras

et al. 1999

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“…The phosphorylation-independent activity of these mutants allowed us to study their activity in isolation from other effectors of PKA at the PEPCK promoter (e.g. AP1) (24,25). In principle, the activation of PEPCK transcription by CREM␣ DIEDML (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cooperative Mechanism of Transcriptional Activation by a Cyclic AMP-response Element Modulator α Mutant Containing a Motif for Constitutive Binding to CREB-binding Protein

Craig¹,

Impey

Goodman

2001

Journal of Biological Chemistry

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Cyclic AMP-response element modulator ␣ (CREM␣) is a transcription factor that is highly related to cAMPresponse element-binding protein (CREB) but represses cAMP-induced gene expression from simple artificial promoters containing a cAMP-response element (CRE). CREM␣ lacks two glutamine-rich Q regions that, in CREB, are thought to be necessary for transcriptional activation. Nevertheless, protein kinase A stimulation induces CREM␣ to activate the complex native promoter in the phosphoenolpyruvate carboxykinase (PEPCK) gene. To study this phenomenon in the absence of protein kinase A stimulation, we introduced a mutation into CREM␣ to allow constitutive binding to the coactivator CREB-binding protein. This mutant, CREM␣ DIEDML , constitutively activated the PEPCK promoter. By engineering the leucine zipper regions of CREM␣ DIEDML and CREB DIEDML to direct their patterns of dimerization, we found that only CREM␣ DIEDML homodimers fully activated the PEPCK promoter. By using a series of deletion and block mutants of the PEPCK promoter, we found that activation by CREM␣ DIEDML depended on the CRE and two CCAAT/enhancer-binding protein (C/EBP) sites. A dominant negative inhibitor of C/EBP, A-C/EBP, suppressed activation by CREM␣ DIEDML . Furthermore, a GAL4-C/EBP␣ fusion protein and CREM␣ DIEDML cooperatively activated a promoter containing three GAL4 sites and the PEPCK CRE. Thus, we propose that the C/EBP sites in the PEPCK promoter allow CREM␣ to activate transcription despite its lack of Q regions.The cyclic AMP-response element modulator (CREM) 1 gene is alternatively spliced to generate multiple transcription factors that mediate the regulation of transcription by cAMP (reviewed in Ref. 1). These CREM factors form homodimers and heterodimers with the related protein CREB that bind specifically to CREs (TGACGTCA) via their conserved C-terminal basic leucine zipper (bZIP) domains (2). Three domains encoded by the CREM and CREB genes contribute to transcriptional activation: the kinase-inducible domain (KID) and two glutamine-rich regions designated as Q-1 and Q-2 (3). Phosphorylation of a serine residue within the KID by PKA allows CREB and CREM to bind to the coactivator CREB-binding protein (CBP) (4, 5). The Q regions are thought to interact with components of the basal transcriptional machinery (6). In CREB, the deletion of the Q-2 region prevents transcriptional activation (7). Moreover, CREM isoforms that lack Q regions have been shown to act as repressors of cAMP-induced transcription (2). These data have lead to the hypothesis that Q regions are required for CREB-mediated transcriptional activation.The CREM␣ isoform contains a KID but lacks both Q regions (2). CREM␣ represses transcription induced by PKA-activated CREB at a minimal promoter containing the somatostatin CRE (2). This repression may be mediated by CREB-CREM␣ heterodimers, which are only weak activators, or by CREM␣ homodimers that cannot activate transcription at the somatostatin CRE (8). These data form the bulk of the evidence for the hypot...

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“…Fos is induced by insulin, and may therefore contribute to the dominant inhibitory effect of insulin. However, as Gurney et al [116] pointed out, fos is also induced by cyclic AMP. This, in turn, could provide an explanation for the biphasic pattern of the cyclic AMP stimulation of the PEPCK promoter (see below).…”

Section: Tissue-specific Controlmentioning

confidence: 97%

“…The P1 site is also detected in in vivo footprinting experiments, but only in cells expressing PEPCK [106]. The junlfos heterodimer binds avidly to the CRE-1 element and, with lower affinity, to the P2, P3 (11) and P4 elements [116]. When HepG2 cells are co-transfected with a jun expression vector and a PEPCK promoter-reporter gene construct, jun stimulates the PEPCK promoter through the CRE-1, P3 (11) ments it inhibits the activation of the PEPCK promoter byjun or by cyclic AMP.…”

Section: Tissue-specific Controlmentioning

confidence: 97%

“…When HepG2 cells are co-transfected with a jun expression vector and a PEPCK promoter-reporter gene construct, jun stimulates the PEPCK promoter through the CRE-1, P3 (11) ments it inhibits the activation of the PEPCK promoter byjun or by cyclic AMP. The inhibitory action offos requires the integrity of site P3(I) [116]. Fos is induced by insulin, and may therefore contribute to the dominant inhibitory effect of insulin.…”

Section: Tissue-specific Controlmentioning

confidence: 99%

See 1 more Smart Citation

Transcriptional control of genes that regulate glycolysis and gluconeogenesis in adult liver

Lemaigre¹,

Rousseau²

1994

Biochemical Journal

100

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Metabolic Regulation of Gene Transcription ,

Cited by 29 publications

References 39 publications

Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras

Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras

Cooperative Mechanism of Transcriptional Activation by a Cyclic AMP-response Element Modulator α Mutant Containing a Motif for Constitutive Binding to CREB-binding Protein

Transcriptional control of genes that regulate glycolysis and gluconeogenesis in adult liver

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