Selective modulation of protein kinase isozymes by the site-selective analog 8-chloroadenosine 3',5'-cyclic monophosphate provides a biological means for control of human colon cancer cell growth.

Ally, Shamsia; Tortora, Giampaolo; Clair, Timothy; Grieco, Domenico; Merlo, Giorgio R.; Katsaros, Dionyssios; Øgreid, D; Døskeland, Stein Ove; Jahnsen, Tore; Cho‐Chung, Yoon S.

doi:10.1073/pnas.85.17.6319

Cited by 71 publications

(31 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the PKA-II isozyme is chiefly cytosolic, RII␣ and RII␤ subunits can enter the nucleus as a component of normal cellular processes or in response to specific stimuli (12)(13)(14)(15). Also, a number of transformed cell lines have been shown to support nuclear localization of ectopically expressed RII␤ (13,16).…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

Protein Kinase A Regulatory Subunit Type IIβ Directly Interacts with and Suppresses CREB Transcriptional Activity in Activated T Cells

Elliott

Tolnay

Tsokos

2003

The Journal of Immunology

View full text Add to dashboard Cite

Levels of the type IIβ regulatory subunit (RIIβ) of protein kinase A are abnormally high in the nuclei of T cells of some subjects with the autoimmune disorder systemic lupus erythematosus (SLE). However, the role of nuclear RIIβ in the regulation of T cell function is unknown. Based on previous studies demonstrating that nuclear protein kinase A-RII subunits can modify cAMP response element (CRE)-dependent transcription, we tested the hypothesis that nuclear RIIβ can alter CRE-directed gene expression in T cells through interaction with the nuclear transcription factor CRE-binding protein CREB. To test this hypothesis, we used the RIIβ-deficient S49 and the Jurkat T cell lines. In both cell lines, transient transfection of RIIβ resulted in nuclear localization of a portion of the ectopically expressed RIIβ. In vitro and in vivo analyses revealed a novel, specific interaction between RIIβ and CREB that mapped to the N-terminal 135 aa of RIIβ. In functional studies, RIIβ inhibited the transcriptional activity of a GAL4-CREB fusion protein by 67% in Jurkat T cells following activation with anti-CD3 and anti-CD28 mAbs. Importantly, deletion of the CREB-binding region of RIIβ completely abrogated inhibition. Additionally, RIIβ suppressed CRE-directed reporter gene expression and substantially reduced induction of promoter activity and endogenous protein levels of the CREB-dependent gene, c-fos, in activated T cells. We conclude that nuclear RIIβ can act as a repressor of CREB transcriptional activity in T cells, providing a potential functional significance for aberrant levels of nuclear RIIβ in systemic lupus erythematosus T cells.

show abstract

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

Protein Kinase A Regulatory Subunit Type IIβ Directly Interacts with and Suppresses CREB Transcriptional Activity in Activated T Cells

Elliott

Tolnay

Tsokos

2003

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…8-Cl-cAMP-treated cancer cells showed a decrease of RI␣ and type I PKA, an increase of RII␤ and type II PKA, and inhibition of cell growth (11)(12)(13). Especially, ras-transformed mouse fibroblast (DT) cells showed morphological differentiation and human leukemic cells showed differentiated characteristics upon the treatment with 8-Cl-cAMP (6,14).…”

mentioning

confidence: 99%

Dual Anticancer Activity of 8-Cl-cAMP: Inhibition of Cell Proliferation and Induction of Apoptotic Cell Death

Kim

Park

et al. 2000

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

“…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.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Selective modulation of protein kinase isozymes by the site-selective analog 8-chloroadenosine 3',5'-cyclic monophosphate provides a biological means for control of human colon cancer cell growth.

Cited by 71 publications

References 29 publications

Protein Kinase A Regulatory Subunit Type IIβ Directly Interacts with and Suppresses CREB Transcriptional Activity in Activated T Cells

Protein Kinase A Regulatory Subunit Type IIβ Directly Interacts with and Suppresses CREB Transcriptional Activity in Activated T Cells

Dual Anticancer Activity of 8-Cl-cAMP: Inhibition of Cell Proliferation and Induction of Apoptotic Cell Death

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

Contact Info

Product

Resources

About