Disruption of Protein Kinase A Regulation Causes Immortalization and Dysregulation of D-Type Cyclins

Nadella, Kiran S.; Kirschner, Lawrence S.

doi:10.1158/0008-5472.can-05-3183

Cited by 65 publications

(78 citation statements)

References 50 publications

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“…At the cellular level, the thinning of ventricular walls was caused by the reduction of cardiomyocyte proliferation. In concordance with the reduced levels of the R1a regulatory subunit, hearts from Prkar1a-CKO mice exhibited enhancement of both free and total PKA activity, similar to the observation in Prkar1a K/K mouse embryonic fibroblasts in vitro (Nadella & Kirschner 2005). However, ablation of Prkar1a did not cause compensation by the other regulatory subunits.…”

Section: Tissue-specific R Subunit Mouse Modelingsupporting

confidence: 74%

“…This observation was interpreted to signify that the majority of the developmental effects were due to excess unregulated PKA activity. These same developmental defects were observed in mice homozygous for a different null allele for Prkar1a, generated by removal of exon 2 from the Prkar1a gene (Kirschner et al 2005).…”

Section: Prkar1a Kossupporting

confidence: 58%

“…In an analysis of 17 animals up to 19 months of age, Veugelers et al reported tumors in 12 mice (57%) consisting primarily of sarcomas and some hepatocellular carcinomas. In an analysis of a larger group of mice up to 2 years old, our group described a somewhat different pattern of tumors, with a spectrum much more similar to those observed in patients with CNC (Kirschner et al 2005). Specifically, we observed osteochondromyxomas in over 80% of mice, schwannomas in 33%, and thyroid tumors in about 10% of animals.…”

Section: Prkar1a Kossupporting

confidence: 56%

“…With use of global gene KO mouse models, the function of each different PKA subunit has been intensively explored in the process of development and physiology, and particularly in tumorigenesis (Brandon et al 1995, Cummings et al 1996, Burton et al 1999, Amieux et al 2002, Rao et al 2004, Veugelers et al 2004, Kirschner et al 2005. However, the utility of these conventional KO mouse models was limited in observing phenotypes due to embryonic or neonatal lethality that prevented analysis of the impact of PKA subunits in postnatal and adult life.…”

Section: Understanding the Function Of Pka Subunits By Targeted Gene mentioning

confidence: 99%

“…Approximately 30-60% of CNC patients will develop cardiac myxomas (Bertherat 2006), and cardiac myxomas are responsible for the death of more than 50% of patients (Stratakis et al 2001). These tumors cannot be recapitulated by conventional Prkar1a KO mice because Prkar1a K/K mice die by e9.5 without the development of heart tube (Amieux et al 2002, Kirschner et al 2005, whereas heterozygotes do not exhibit a cardiac phenotype (Veugelers et al 2004, Kirschner et al 2005. In order to better understand the tumorigenesis of cardiac myxoma, we generated heart-specific Prkar1a KO mouse model (Prkar1a-CKO) by utilizing the Cre-loxP system (Yin et al 2008a,b), in which a-myosin heavy chain (a-MHC) was used as the promoter to drive the expression of cre recombinase.…”

Section: Tissue-specific R Subunit Mouse Modelingmentioning

confidence: 99%

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Mouse models of altered protein kinase A signaling

Kirschner¹,

Yin²,

Jones³

et al. 2009

Endocrine-Related Cancer

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Protein kinase A (PKA) is an evolutionarily conserved protein which has been studied in model organisms from yeast to man. Although the cAMP-PKA signaling system was the first mammalian second messenger system to be characterized, many aspects of this pathway are still not well understood. Owing to findings over the past decade implicating PKA signaling in endocrine (and other) tumorigenesis, there has been renewed interest in understanding the role of this pathway in physiology, particularly as it pertains to the endocrine system. Because of the availability of genetic tools, mouse modeling has become the pre-eminent system for studying the physiological role of specific genes and gene families as a means to understanding their relationship to human diseases. In this review, we will summarize the current data regarding mouse models that have targeted the PKA signaling system. These data have led to a better understanding of both the complexity and the subtlety of PKA signaling, and point the way for future studies, which may help to modulate this pathway for therapeutic effect.

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Section: Tissue-specific R Subunit Mouse Modelingsupporting

confidence: 74%

Section: Prkar1a Kossupporting

confidence: 58%

Section: Prkar1a Kossupporting

confidence: 56%

Section: Understanding the Function Of Pka Subunits By Targeted Gene mentioning

confidence: 99%

Section: Tissue-specific R Subunit Mouse Modelingmentioning

confidence: 99%

See 3 more Smart Citations

Mouse models of altered protein kinase A signaling

Kirschner¹,

Yin²,

Jones³

et al. 2009

Endocrine-Related Cancer

View full text Add to dashboard Cite

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Mitogenic signaling pathways induced by G protein‐coupled receptors

Rozengurt

2007

Journal Cellular Physiology

417

402

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G protein-coupled receptor (GPCR) agonists, including neurotransmitters, hormones, chemokines, and bioactive lipids, act as potent cellular growth factors and have been implicated in a variety of normal and abnormal processes, including development, inflammation, and malignant transformation. Typically, the binding of an agonistic ligand to its cognate GPCR triggers the activation of multiple signal transduction pathways that act in a synergistic and combinatorial fashion to relay the mitogenic signal to the nucleus and promote cell proliferation. A rapid increase in the activity of phospholipases C, D, and A2 leading to the synthesis of lipid-derived second messengers, Ca 2þ fluxes and subsequent activation of protein phosphorylation cascades, including PKC/PKD, Raf/MEK/ERK, and Akt/ mTOR/p70S6K is an important early response to mitogenic GPCR agonists. The EGF receptor (EGFR) tyrosine kinase has emerged as a transducer in the signaling by GPCRs, a process termed transactivation. GPCR signal transduction also induces striking morphological changes and rapid tyrosine phosphorylation of multiple cellular proteins, including the non-receptor tyrosine kinases Src, focal adhesion kinase (FAK), and the adaptor proteins CAS and paxillin. The pathways stimulated by GPCRs are extensively interconnected by synergistic and antagonistic crosstalks that play a critical role in signal transmission, integration, and dissemination. The purpose of this article is to review recent advances in defining the pathways that play a role in transducing mitogenic responses induced by GPCR agonists.

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Leptin potentiates antiproliferative action of cAMP elevation via protein kinase A down‐regulation in breast cancer cells

Naviglio

Gesto

Illiano

et al. 2010

Journal Cellular Physiology

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Previously, we have shown that leptin potentiates the antiproliferative action of cAMP elevating agents in breast cancer cells and that the protein kinase A (PKA) inhibitor KT-5720 prevented the antiproliferative effects induced by the leptin plus cAMP elevation. The present experiments were designed to gain a better understanding about the PKA role in the antitumor interaction between leptin and cAMP elevating agents and on the underlying signaling pathways. Here we show that exposure of MDA-MB-231 breast cancer cells to leptin resulted in a strong phosphorylation of both ERK1/2 and STAT3. Interestingly, intracellular cAMP elevation upon forskolin pretreatment completely abrogated both ERK1/2 and STAT3 phosphorylation in response to leptin and was accompanied by a consistent CREB phosphorylation. Notably, leptin plus forskolin cotreatments resulted in a strong decrease of both PKA regulatory RIα and catalytic subunits protein levels. Importantly, pretreatment with the PKA inhibitor KT-5720 blocked the forskolin-induced CREB phosphorylation and prevented both the inhibition by forskolin of leptin-induced ERK1/2 and STAT3 phosphorylation and the PKA subunits down-regulation induced by the combination of leptin and forskolin. Altogether, our results indicate that leptin-dependent signaling pathways are influenced by cAMP elevation and identify PKA as relevantly involved in the pharmacological antitumor interaction between leptin and cAMP elevating drugs in MDA-MB-231 cells. We propose a molecular model by which PKA confers its effects. Potential therapeutic applications by our data will be discussed.

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Disruption of Protein Kinase A Regulation Causes Immortalization and Dysregulation of D-Type Cyclins

Cited by 65 publications

References 50 publications

Mouse models of altered protein kinase A signaling

Mouse models of altered protein kinase A signaling

Mitogenic signaling pathways induced by G protein‐coupled receptors

Leptin potentiates antiproliferative action of cAMP elevation via protein kinase A down‐regulation in breast cancer cells

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