Sp1 Transcription Factor as a Molecular Target for Nitric Oxide– and Cyclic Nucleotide–Mediated Suppression of cGMP-Dependent Protein Kinase-Iα Expression in Vascular Smooth Muscle Cells

Hassan, Sazzad; Yang, Xiangli; Cao, Xu; Cornwell, Trudy L.; Soff, Gerald A.; Lincoln, Thomas M.

doi:10.1161/hh0402.105898

Cited by 62 publications

(51 citation statements)

References 39 publications

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“…In the NO/sGC signaling pathways, Sp1 is important for the basal activity of endothelial (Wu 2002) and neuronal (Saur et al 2002, Bachir et al 2003 NO synthases. Moreover, it is also involved in the regulation of human type I protein kinase G gene expression (Sellak et al 2002). Together with the findings presented here, these observations indicated the importance of Sp1 in the NO/sGC signaling.…”

Section: Discussionsupporting

confidence: 87%

Molecular cloning and characterization of α1-soluble guanylyl cyclase gene promoter in rat pituitary cells

Jiang

Stojilković

2006

Journal of Molecular Endocrinology

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Soluble guanylyl cyclase is a cytosolic enzyme which catalyzes conversion of GTP to the second messenger cyclic GMP. The transcriptional regulation at the promoter levels of four soluble guanylyl cyclase subunits, termed a1, a2, b1, and b2, is largely unknown. In this study, we identified the transcription start site of a1-soluble guanylyl cyclase gene in rat pituitary cells and cloned the 3 . 5 kb 5 0 -promoter. Sequence analysis of this TATA-less promoter revealed the presence of several putative-binding sites for transcriptional factors, including CCAAT site at K41 to K32 and Sp1 site at K34 to K24. Transfection of pituitary cells with constructs of variable lengths confirmed the relevance of different promoter regions in the control of transcriptional activity. Among them, the K49 to C156 region was critical for basal transcriptional activity. Electrophoretic mobility shift assay using nuclear proteins extracted from normal and immortalized pituitary cells indicated that the CCAAT/Sp1 site within the K49 to C156 region was able to specifically interact with CCAAT-binding factor and Sp1. These two sites were partly overlapped and both of them conferred stimulatory effects. The in vivo recruitment of CCAAT-binding factor and Sp1 was confirmed by chromatin immunoprecipitation. These results indicate that the composite CCAAT/Sp1 cis-element contributes to the expression of a1-sGC subunit in resting pituitary cells.

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Section: Discussionsupporting

confidence: 87%

Molecular cloning and characterization of α1-soluble guanylyl cyclase gene promoter in rat pituitary cells

Jiang

Stojilković

2006

Journal of Molecular Endocrinology

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“…Its expression is differently regulated in tumors and in normal tissue (14,43,44). In mammalian cells, two different genes encode type I and II PKGs (45).…”

Section: Discussionmentioning

confidence: 99%

Type II, but not type I, cGMP-dependent protein kinase reverses bFGF-induced proliferation and migration of U251 human glioma cells

Cao

Yan

Sang

et al. 2013

Molecular Medicine Reports

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Abstract.Previous data have shown that the type II cGMP-dependent protein kinase (PKG II) inhibits the EGF-induced MAPK signaling pathway. In order to thoroughly investigate PKG, it is necessary to elucidate the function of another type of PKG, PKG I. The aim of this study was to investigate the possible inhibitory effect of PKG II and PKG I activity on the basic fibroblast growth factor (bFGF)-induced proliferation and migration of U251 human glioma cells and the possible underlying mechanisms. U251 cells were infected with adenoviral constructs encoding cDNA of PKG I (Ad-PKG I) or PKG II (Ad-PKG II) to increase the expression levels of PKG I or PKG II and then treated with 8-Br-cGMP and 8-pCPT-cGMP, respectively, to activate the enzyme. An MTT assay was used to detect the proliferation of the U251 cells. The migration of the U251 cells was analyzed using a Transwell migration assay. Western blot analysis was used to detect the phosphorylation/activation of the fibroblast growth factor receptor (FGFR), MEK and ERK and the nuclear distribution of p-ERK. The results showed that bFGF treatment increased the proliferation and migration of U251 cells, accompanied by increased phosphorylation of FGFR, MEK and ERK. Furthermore, the nuclear distribution of p-ERK increased following bFGF treatment. Increasing the activity of PKG II through infection with Ad-PKG II and stimulation with 8-pCPT-cGMP significantly attenuated the aforementioned effects of the bFGF treatment, while increased PKG I activity did not inhibit the effects of bFGF treatment. These data suggest that increased PKG II activity attenuates bFGF-induced proliferation and migration by inhibiting the MAPK/ERK signaling pathway, whereas PKG I does not. IntroductionBasic fibroblast growth factor (bFGF) is a multifunctional growth factor involved in tumor development, including cell differentiation, cell growth, migration, angiogenesis and tumor formation (1-4). Its biological effects have been reported to be exerted mainly through interaction with its high-affinity receptor, fibroblast growth factor receptor 1 (FGFR1) (5-8). Narong and Leelawat (9) reported that bFGF enhances the migration of cholangiocarcinoma cells by the phosphorylation of MEK1/2. Results from previous studies have shown that bFGF signaling plays a key role in the development of cancer, including gastric, lung and endometrial cancer (10-12).The cGMP-dependent protein kinases (PKGs) are serine/threonine kinases and include two types of PKGs, PKG I and PKG II (13,14). PKG I is widely distributed within the body and its expression levels are lower in various tumor tissues. PKG II is more tissue-restricted and is characterized by reduced expression levels in many types of tumor cells (15). PKG I leads to decreased tumor growth and invasiveness in many types of cells, including cardiomyocytes, mesangial cells and neutrophils (16)(17)(18)(19). PKG I has been identified to be a tumor suppressor (20). Previous studies suggest that PKG II has a role in the regulation of cell proliferation and apo...

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“…Various Sp1 phosphorylations have been documented to increase both Sp1 binding to GC-box and transactivation activity; these include serine phosphorylation by protein kinase C-␥ (PKC-␥), 21 Ser 59 phosphorylation by cyclin A-dependent kinase 2, 25 as well as Thr 453 and Thr 739 phosphorylation by p42/p44 26 Furthermore, Sp1 also has been shown to undergo phosphorylation by PKA 27,28 ; however, although this phosphorylation increased its GC-box binding, it converted Sp1 to a repressor of gene expression. This is consistent with studies in which certain phosphorylations conferred upon Sp1 a transcriptional repression activity.…”

Section: Discussionmentioning

confidence: 99%

“…24 Whereas various Sp1 phosphorylations have been documented to increase its DNA binding and transactivation activity, 21,25,26 a few reports suggested that certain phosphorylations compromise Sp1 binding and transactivation activity. 17,18 Furthermore, Sp1 has been shown to undergo phosphorylation by cAMP-dependent protein kinase (PKA), 27,28 in which case the phosphorylation increased its GC-box-binding capability but rendered it a repressor of gene expression. Consistently, alternative phosphorylations also have been reported to render Sp1 a transcriptional repressor.…”

Section: Introductionmentioning

confidence: 99%

“…STARK 11 Since it has been shown that Sp1 undergoes a PKA-dependent phosphorylation, 19,27,28 the possibility that the PKA pathway is involved in the generation of the inhibitory phosphorylation of Sp1 was explored. Treatment of antifolate-resistant cells with various cAMP-reactive agents, including cholera toxin, forskolin (data not shown), and dibutyryl cAMP (Bt 2 cAMP) ( Figure 3A) had no effect on the DNA binding capability of Sp1.…”

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Loss of Sp1 function via inhibitory phosphorylation in antifolate-resistant human leukemia cells with down-regulation of the reduced folate carrier

Stark

Assaraf

2006

Blood

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Sp1 Transcription Factor as a Molecular Target for Nitric Oxide– and Cyclic Nucleotide–Mediated Suppression of cGMP-Dependent Protein Kinase-Iα Expression in Vascular Smooth Muscle Cells

Cited by 62 publications

References 39 publications

Molecular cloning and characterization of α1-soluble guanylyl cyclase gene promoter in rat pituitary cells

Molecular cloning and characterization of α1-soluble guanylyl cyclase gene promoter in rat pituitary cells

Type II, but not type I, cGMP-dependent protein kinase reverses bFGF-induced proliferation and migration of U251 human glioma cells

Loss of Sp1 function via inhibitory phosphorylation in antifolate-resistant human leukemia cells with down-regulation of the reduced folate carrier

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