Cyclic AMP signalling and cellular proliferation: regulation of CREB and CREM

Fazia, Maria Agnese Della; Servillo, Giuseppe; Sassone–Corsi, Paolo

doi:10.1016/s0014-5793(97)00445-6

Cited by 105 publications

(73 citation statements)

References 21 publications

(30 reference statements)

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“…6A). These observations are consistent with previous studies of cAMP and CREB activation after PH (13).…”

Section: Relationship Between Prostaglandin Signaling and Camp-signalingsupporting

confidence: 94%

“…Previous studies have shown that the cytokine-signaling pathway initiated by TNF␣ and IL-6 and mediated by the transcription factor STAT3 plays an important role in liver regeneration (3,13,14). To determine whether prostaglandins function as part of this signaling pathway during liver regeneration, we used two different experimental strategies.…”

Section: Relationship Between Prostaglandin Metabolism and Cytokine Sig-mentioning

confidence: 99%

“…The molecular mechanisms that regulate these events include early signaling events such as increased production of hepatocyte growth factor (5), TNF␣, and IL-6 (6), followed by induction of a number of immediate early genes (7). Subsequent changes occur in the activity of several transcription factors, including increased activity of NF B, AP-1, signal transducer and activator of transcription-3 (STAT3), CREB, and CCAAT enhancer binding protein ␤ (C͞EBP␤) and decreased activity of C͞EBP␣ (8)(9)(10)(11)(12)(13). The transcription factor STAT3 has been shown to be specifically activated after PH by gel shift analysis of hepatic nuclear extracts (8).…”

mentioning

confidence: 99%

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Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration

Rudnick

Perlmutter

Muglia

2001

Proc. Natl. Acad. Sci. U.S.A.

121

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The liver responds to multiple types of injury with an extraordinarily well orchestrated and tightly regulated form of regeneration. The response to partial hepatectomy has been used as a model system to elucidate the molecular basis of this regenerative response. In this study, we used cyclooxygenase (COX)-selective antagonists and -null mice to determine the role of prostaglandin signaling in the response of liver to partial hepatectomy. The results show that liver regeneration is markedly impaired when both COX-1 and COX-2 are inhibited by indocin or by a combination of the COX-1 selective antagonist, SC-560, and the COX-2 selective antagonist, SC-236. Inhibition of COX-2 alone partially inhibits regeneration whereas inhibition of COX-1 alone tends to delay regeneration. Neither the rise in IL-6 nor the activation of signal transducer and activator of transcription-3 (STAT3) that is seen during liver regeneration is inhibited by indocin or the selective COX antagonists. In contrast, indocin treatment prevents the activation of CREB by phosphorylation that occurs during hepatic regeneration. These data indicate that prostaglandin signaling is required during liver regeneration, that COX-2 plays a particularly important role but COX-1 is also involved, and implicate the activation of CREB rather than STAT3 as the mediator of prostaglandin signaling during liver regeneration.

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“…6A). These observations are consistent with previous studies of cAMP and CREB activation after PH (13).…”

Section: Relationship Between Prostaglandin Signaling and Camp-signalingsupporting

confidence: 94%

Section: Relationship Between Prostaglandin Metabolism and Cytokine Sig-mentioning

confidence: 99%

mentioning

confidence: 99%

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Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration

Rudnick

Perlmutter

Muglia

2001

Proc. Natl. Acad. Sci. U.S.A.

121

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“…Liver regeneration following PH has proved a powerful model system to understand the signals initiating and controlling cellular proliferation. cAMP fluxes are well documented to accompany the first rounds of hepatocyte cell division (Diehl et al 1992;Della Fazia et al 1997), but the cellular mechanism by which this second messenger operates has remained elusive. The powerful induction in CREM expression following hepatectomy that we have documented recently suggests that it may play an important regulatory role.…”

Section: Resultsmentioning

confidence: 99%

Transcription factor CREM coordinates the timing of hepatocyte proliferation in the regenerating liver

Servillo¹,

Fazia²,

Sassone–Corsi³

1998

Genes Dev.

Self Cite

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The liver regenerates upon partial hepatectomy (PH) as terminally differentiated hepatocytes undergo a tremendous proliferative process. CREM gene expression is powerfully induced during liver regeneration. We show that cell proliferation is significantly reduced upon PH in CREM −/− mice. There is a reduction in DNA synthesis, in the number of mitosis and of phosphorylated histone H3-positive cells. The post-PH proliferation peak is delayed by 10 hr, indicating an altered hepatocyte cell cycle. Expression of cyclins A, B, D1, E, and cdc2, of c-fos and tyrosine aminotransferase is deregulated. CREM mutation results in delayed S-phase entry, impairing the synchronization of proliferation. Received September 10, 1998; revised version accepted October 15, 1998. The liver is one of the most important organs for homeostasis in mammals. Among its properties is the remarkable ability to regenerate following partial hepatectomy (Michalopoulos 1990;Fausto 1994). As much as 70% of the liver can be surgically removed and hepatocytes will proliferate to fully regenerate the original cell mass. The initial rounds of cell division are synchronous, and the first DNA replication occurs within 24 hr of surgery in the rat. The regeneration process is completed within 10-15 days (Bucher 1963).A number of hormones, growth factors, and cytokines and their coupled signal transduction pathways have been implicated in governing hepatocyte proliferation, but the precise orchestration of these factors is poorly understood (Diehl and Rai 1996;Michalopoulos and De Frances 1997). In particular, cytokines IL-6 and TNF have been implicated in initiating hepatocyte DNA synthesis during regeneration (Fausto et al. 1995;Cressman et al. 1996;Yamada et al. 1997), whereas the DNA-binding activity of the downstream transcription factors Stat3 and NF-B increases during the first hours following hepatectomy (Taub 1996).A characteristic feature of liver regeneration is the dramatic increase in intracellular cAMP levels during the hepatocyte proliferation process, although its significance has remained elusive (Diehl et al. 1992). cAMP peaks during the first hours following partial hepatectomy, whereas elevated levels of cAMP also correlate with the proliferation of liver cell at birth (Diehl and Rai 1996). These notions underscore the critical role that must be played by cAMP-responsive transcription factors in liver regeneration.Transcription factors coupled to cAMP signaling constitute a family of closely related bZIP proteins, either activators or repressors, binding to cAMP-responsive promoter elements (CREs) located within the regulatory regions of cAMP-inducible genes (Sassone-Corsi 1995; Montminy 1997). The factors CREB (CRE-binding protein), CREM (CRE modulator), and ATF-1 (activator transcription factor 1) are turned into activators by phosphorylation at a serine residue (Ser-133 in CREB; Ser-117 in CREM) (Gonzalez and Montminy 1989;De Groot et al. 1993) elicited by PKA and other kinases (SassoneCorsi 1995;Montminy 1997). Interestingly, a C...

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“…The CREM gene has been attributed a role in the regulation of cell proliferation and regeneration (52)(53)(54). In the homozygous CREM-null mouse, liver regeneration is impaired, implicating CREM gene products in the regulation of tissue regeneration (52).…”

Section: Discussionmentioning

confidence: 99%

Glucagon stimulates expression of the inducible cAMP early repressor and suppresses insulin gene expression in pancreatic beta-cells.

2000

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The hormone glucagon is secreted by the ␣-cells of the endocrine pancreas (islets of Langerhans) during fasting and is essential for the maintenance of blood glucose levels by stimulation of hepatic glucose output. Excessive production and secretion of glucagon by the ␣-cells of the islets is a common accompaniment to diabetes. The resulting hyperglucagonemia stimulates hepatic glucose production, thereby contributing to hyperglycemia of diabetes. The reduced insulin secretion in diabetes and resultant failure to suppress glucagon secretion by intra-islet paracrine mechanisms is believed to cause the hypersecretion of glucagon. Here, we report the discovery of a new mechanism by which glucagon suppresses insulin secretion. We show that glucagon, but not glucagon-like peptide 1 (GLP-1)

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Cyclic AMP signalling and cellular proliferation: regulation of CREB and CREM

Cited by 105 publications

References 21 publications

Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration

Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration

Transcription factor CREM coordinates the timing of hepatocyte proliferation in the regenerating liver

Glucagon stimulates expression of the inducible cAMP early repressor and suppresses insulin gene expression in pancreatic beta-cells.

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