Site-Selective Cyclic AMP Analogs as New Biological Tools in Growth Control, Differentiation, and Proto-oncogene Regulation

Cho‐Chung, Yoon S.; Clair, Timothy; Tagliaferri, P; Ally, Shamsia; Katsaros, Dionyssios; Tortora, Giampaolo; Neckers, Leonard Μ.; Avery, Thomas L.; Crabtree, Gerald W.; Robins, Roland K.

doi:10.3109/07357908909038282

Cited by 85 publications

(49 citation statements)

References 56 publications

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“…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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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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“…6 G) (51). These studies have demonstrated an immediate translocation of RII13 to the nucleus, followed by a decrease in RIa protein and mRNA (22,25,26,51). Thus, we evaluated the levels of the RIa and RIIP subunits by photoaffinity labeling followed by immunoprecipitation.…”

Section: Methodsmentioning

confidence: 99%

“…In the normal setting, cAMP binds to two sites on the regulatory subunits and results in dissociation of mainly type I PKA, releasing the catalytic subunit from the regulatory subunit (RI), thereby activating the enzyme for phosphorylation of various proteins. 8-Cl-cAMP binds to the two sites on RI with a higher affinity than cAMP and results in activation of the type I PKA, with subsequent downregulation of both the protein and mRNA for RI (22,(25)(26)(27)(28). 8-Cl-cAMP also binds, with a high affinity, one of the two sites of RII, but binds the other poorly.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of mdr-1 expression by 8-Cl-cAMP in multidrug resistant MCF-7 human breast cancer cells.

Scala¹,

Budillon²,

Zhan

et al. 1995

J. Clin. Invest.

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8-Cl-cAMP, a site-selective analogue of cAMP, decreased mdr-1 expression in multidrug-resistant human breast cancer cells. A sixfold reduction of mdr-1 mRNA expression by 8-Cl-cAMP began within 8 h of treatment and was associated with a decrease in the synthesis of P-glycoprotein and with an increase in vinblastine accumulation. A reduction in mdr-1 expression after 8-Cl-cAMP treatment was also observed in multidrug-resistant human ovarian cancer cell lines. 8-Cl-cAMP is known to change the ratio between the two regulatory subunits, RI and RH, of protein kinase A (PKA). We observed that RIa decreased within 24 h of 8-Cl-cAMP treatment, that RIIP increased after as few as 3 h of treatment, and that PKA catalytic activity remained unchanged during 48 h of 8-Cl-cAMP treatment. The results are consistent with the hypothesis that mdr-1 expression is regulated in part by changes in PKA isoenzyme levels. Although 8-Cl-cAMP has been used to differentiate cells in other model systems, the only differentiating effect that could be detected after 8-Cl-cAMP treatment in the MCF-7TH cells was an increase in cytokeratin expression. Evidence that the reduction of mdr-1 mRNA occurred at the level of gene transcription was obtained by measuring chloramphenicol acetyltransferase (CAT) mRNA in MCF-7TH cells transfected with an mdr-1 promoter-CAT construct prior to 8-Cl-cAMP treatment. Thus, 8-Cl-cAMP is able to downregulate mdr-1 expression and suggests a new approach to reversal of drug resistance in human breast cancer. (J. Clin.

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“…Thus although many of the changes in cAMP dependent gene expression are due to the phosphorylation and activation of transcription factors by the catalytic subunit of PK-A (Ziff, 1990) there is increasing evidence that the regulatory cAMP binding subunits play an independent or modulating role. Interestingly, the ability of cAMP analogs to reverse the malignant phenotype of a number of cell lines including those derived from human colorectal cancer is associated with changes in the expression of cAMP binding proteins and the movement of binding proteins in to the nucleus (Cho-Chung et al, 1989). Cyclic AMP binding proteins may therefore have an important role in controlling the expression of genes involved in development of the malignant state.…”

Section: Methodsmentioning

confidence: 99%

Cyclic adenosine 3',5'-monophosphate binding proteins in human colorectal cancer and mucosa

Bradbury

Miller²,

Dc³

1991

Br J Cancer

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Summary Cyclic AMP Binding Proteins (cAMP-BP) levels have been measured by means of a competitive binding assay in the cytosols of 50 human colorectal cancers. These levels have been related to those in mucosa both adjacent to and distant from the tumour in the same patients. Cyclic AMP-BP were higher in tumour than in either adjacent (P<0.000001) or distant mucosa (P<0.00001). Binding of cAMP in adjacent mucosa was lower than that in distant mucosa (P<0.0001). There was no significant difference in the level of binding between tumours arising from different sites in the colon and binding was not related to age or sex of the patient. However, binding was higher in Dukes' B than Dukes' C cancers (P<0.005). There was also a trend for cAMP binding levels to be higher in moderately differentiated than in poorly differentiated cancers (P = 0.07). Thus cAMP-BP appear to be over-expressed in human colorectal cancers and levels are related to the stage and grade.Cyclic adenosine 3',5'-monophosphate (cAMP) functions as a secondary messenger for a wide range of hormones releasing factors and drugs. The cAMP signalling system also interacts with other signalling pathways that are used by locally-acting growth factors (Olashaw & Pledger, 1988) to bring about co-ordinated control of basic cell processes such as proliferation and differentiation. Cyclic AMP exerts all its known effects through binding to and activating a specific cAMPdependent protein kinase, also known as Protein Kinase A (PK-A) (Taylor et al., 1989). PK-A is a tetrameric holoenzyme comprising two regulatory units (R), and two catalytic units (C). R units, also known as cAMP binding proteins (cAMP-BP) act as pseudosubstrate for the C units and so prevent them from carrying out phosphorylation within the cell (Shenolikar, 1988). Activation of PK-A follows binding of cAMP to R units and their dissociation from the C unit. As well as leading to protein phosphorylation, activation PK-A also brings about changes in expression of cAMP dependent genes, although the exact mechanisms are, as yet, unclear (Roesler et al., 1988). Conventionally, cAMP has been considered a negative signal to cellular proliferation although stimulatory effects have been described depending on the cell type, phase in the cell cycle and presence of other growth factors (Dumont et al., 1989). Cyclic AMP analogues have been shown to inhibit the growth and promote the differentiation of a number of human cancer cell lines in vitro including those derived from colorectal cancer (Ally et al., 1988). In animal studies the production of colonic tumours by chemical carcinogens has been associated with decreased levels of PK-A activity (DeRubertis & Craven, 1980). Furthermore, cAMP and cAMP-dependent protein kinase levels have been reported to be lower in human colorectal cancers and villous adenomas than in normal mucosa (Alexandrov et al., 1986). By contrast, in breast cancer cAMP-BP levels are of independent prognostic significance (Miller et al., 1990) with higher levels of binding being associ...

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Site-Selective Cyclic AMP Analogs as New Biological Tools in Growth Control, Differentiation, and Proto-oncogene Regulation

Cited by 85 publications

References 56 publications

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

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

Downregulation of mdr-1 expression by 8-Cl-cAMP in multidrug resistant MCF-7 human breast cancer cells.

Cyclic adenosine 3',5'-monophosphate binding proteins in human colorectal cancer and mucosa

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