α1-Adrenergic Receptor Subtypes Differentially Control the Cell Cycle of Transfected CHO Cells through a cAMP-dependent Mechanism Involving p27

Shibata, Katsushi; Katsuma, Susumu; Koshimizu, Taka-aki; Shinoura, Hitomi; Hirasawa, Akira; Tanoue, Akito; Tsujimoto, Gozoh

doi:10.1074/jbc.m201375200

Cited by 28 publications

(26 citation statements)

References 33 publications

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“…Effects of ␣ 1A -AR Agonists on cAMP Accumulation. All three ␣ 1 -AR subtypes promote agonist-stimulated G q activation and Ca 2ϩ release, but only the ␣ 1A -and ␣ 1B -AR stimulate adenylate cyclase and cAMP production (Shibata et al, 2003). This suggests that the receptor coupling determinants for the Ca 2ϩ and cAMP pathways differ, and thus that the immediate postreceptor step for each of these pathways is distinct.…”

Section: Resultsmentioning

confidence: 87%

Quantification of Functional Selectivity at the Human α1A-Adrenoceptor

Evans

Broxton

Merlin

et al. 2011

Molecular Pharmacology

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Although G protein-coupled receptors are often categorized in terms of their primary coupling to a given type of G␣ protein subunit, it is now well established that many show promiscuous coupling and activate multiple signaling pathways. Furthermore, some agonists selectively activate signaling pathways by promoting interaction between distinct receptor conformational states and particular G␣ subunits or alternative signaling proteins. We have tested the capacity of agonists to stimulate Ca 2ϩ release, cAMP accumulation, and changes in extracellular acidification rate (ECAR) at the human ␣ 1A -adrenoceptor. Signaling bias factors were determined by novel application of an operational model of agonism and compared with the reference endogenous agonist norepinephrine; values significantly different from 1.0 indicated an agonist that promoted receptor conformations distinct from that favored by norepinephrine. Oxymetazoline was a full agonist for ECAR and a partial agonist for Ca 2ϩ release (bias factor 8.2) but failed to stimulate cAMP production. Phenylephrine showed substantial bias toward ECAR versus Ca 2ϩ release or cAMP accumulation (bias factors 21 and 33, respectively) but did not display bias between Ca 2ϩ and cAMP pathways. Cirazoline and N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide (A61603) displayed bias toward cAMP relative to Ca 2ϩ release (bias factors of 7.4 and 8.6). It is noteworthy that epinephrine, a second endogenous adrenoceptor agonist, did not display bias relative to norepinephrine. Our finding that phenylephrine displayed significant signaling bias, despite being highly similar in structure to epinephrine, indicates that subtle differences in agonist-receptor interaction can affect conformational changes in cytoplasmic domains and thereby modulate the repertoire of effector proteins that are activated.

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Section: Resultsmentioning

confidence: 87%

Quantification of Functional Selectivity at the Human α1A-Adrenoceptor

Evans

Broxton

Merlin

et al. 2011

Molecular Pharmacology

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“…The α 1B AR can regulate the cell cycle through cdk-6-and cyclin E-associated kinases, but the α 1B AR effect on proliferation may be cell-type specific (Gonzalez-Cabrera et al 2004). For example, in CHO cells transfected with the α 1B AR, the cell cycle was stopped when activated by phenylephrine (Shibata et al 2003). In TRAMP cells which expressed mostly the α 1B AR subtype, doubling time was faster with decreasing α 1B AR and increasing α 1A AR and α 1D AR expression (Shi et al 2007).…”

Section: Discussionmentioning

confidence: 99%

“…In most cell types studied, the α 1A AR subtype increases the levels of the cdk inhibitor p27Kip1 and halts the cell cycle at the G1-S checkpoint (Shibata et al 2003;Saeed et al 2004;Gonzalez-Cabrera et al 2004). In our study, there was a significant reduction in cancer incidence in CAM-α 1A AR mice, which could be due to this cell cycle stoppage.…”

Section: Discussionmentioning

confidence: 99%

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

Collette

Amoth

et al. 2014

AGE

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The α 1 -adrenergic receptor (α 1 AR) subtypes, α 1A AR and α 1B AR, have differential effects in the heart and central nervous system. Long-term stimulation of the α 1A AR subtype prolongs lifespan and provides cardio-and neuro-protective effects. We examined the lifespan of constitutively active mutant (CAM)-α 1B AR mice and the incidence of cancer in mice expressing the CAM form of either the α 1A AR (CAM-α 1A AR mice) or α 1B AR. CAM-α 1B AR mice have a significantly shortened lifespan when compared with wild-type (WT) animals; however, the effect was sex dependent. Female CAM-α 1B AR mice lived significantly shorter lives, while the median lifespan of male CAM-α 1B AR mice was not different when compared with that of WT animals. There was no difference in the incidence of cancer in either sex of CAM-α 1B AR mice. The incidence of cancer was significantly decreased in CAM-α 1A AR mice when compared with that in WT, and no sex-dependent effects were observed. Further study is warranted on cancer incidence after activation of each α 1 AR subtype and the effect of sex on lifespan following activation of the α 1B AR. The implications of a decrease in cancer incidence following long-term α 1A AR stimulation could lead to improved treatments for cancer.

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“…Alpha1-adrenergic receptors are members of the superfamily of G protein-coupled receptors and mediate effects related to the regulation of cellular hypertrophy and proliferation (Cruise et al, 1985;Lefkowitz and Caron, 1988;Cotecchia et al, 1990;Thonberg et al, 1994;Spector et al, 1997). Three distinct subtypes of alpha1-adrenergic receptors (alpha1A-(ADRA1A), alpha1B-(ADRA1B), and alpha1D-(ADRA1D) adrenergic receptors) have a prominent role in cell growth, and activation of ADRA1A and ADRA1B inhibits serum-prompted cell proliferation (Auer et al, 1998;Shibata et al, 2003). ADRA1B can activate the cyclin-dependent kinase inhibitors p27KIP1 and p21Cip1/WAF1, thereby inhibiting cell proliferation through this pathway (Auer et al, 1998;Shibata et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Three distinct subtypes of alpha1-adrenergic receptors (alpha1A-(ADRA1A), alpha1B-(ADRA1B), and alpha1D-(ADRA1D) adrenergic receptors) have a prominent role in cell growth, and activation of ADRA1A and ADRA1B inhibits serum-prompted cell proliferation (Auer et al, 1998;Shibata et al, 2003). ADRA1B can activate the cyclin-dependent kinase inhibitors p27KIP1 and p21Cip1/WAF1, thereby inhibiting cell proliferation through this pathway (Auer et al, 1998;Shibata et al, 2003). Reduced ADRA1B expression might thus disrupt this pathway, giving cells aberrant growth advantage.…”

Section: Discussionmentioning

confidence: 99%

Frequent reduced expression of alpha-1B-adrenergic receptor caused by aberrant promoter methylation in gastric cancers

et al. 2007

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Recent studies have suggested that epigenetic inactivation of tumour-related genes by promoter methylation participates in the development of gastric cancer. We newly identified the frequently aberrant promoter methylation of alpha-1B-adrenergic receptor (ADRA1B) in colorectal cancer by methylation-sensitive representational difference analysis (MS-RDA) and examined the methylation status of the ADRA1B promoter in 34 paired samples of colorectal cancer and surrounding epithelial tissue, and 34 paired samples of gastric cancer and surrounding epithelial tissue. In colorectal cancers, only four of 34 (11.8%) tumours showed ADRA1B promoter methylation. In contrast, ADRA1B promoter methylation was detected in 24 of 34 (70.6%) gastric cancers and in 14 of 34 (41.2%) surrounding epithelial tissues. The frequency of ADRA1B promoter methylation was higher in gastric epithelial tissues with intestinal metaplasia (41.6%) than in those without intestinal metaplasia (25.0%). Reverse transcription -PCR detected reduced ADRA1B expression in 12 of 18 (66.7%) gastric cancers, and its promoter methylation was detected in 11 of these 12 (91.7%) gastric cancers with reduced ADRA1B expression. Thus, ADRA1B promoter is frequently methylated in gastric cancer. Our results suggest that the ADRA1B gene is an important tumour-related gene frequently involved in the development and progression of gastric cancer.

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α1-Adrenergic Receptor Subtypes Differentially Control the Cell Cycle of Transfected CHO Cells through a cAMP-dependent Mechanism Involving p27

Cited by 28 publications

References 33 publications

Quantification of Functional Selectivity at the Human α1A-Adrenoceptor

Quantification of Functional Selectivity at the Human α1A-Adrenoceptor

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

Frequent reduced expression of alpha-1B-adrenergic receptor caused by aberrant promoter methylation in gastric cancers

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