Background: Previous studies of patients with acute leukemia showed that plasma cGMP levels were markedly elevated before treatment, fell after successful therapy but increased after relapse. In many cells high concen...Background: Previous studies of patients with acute leukemia showed that plasma cGMP levels were markedly elevated before treatment, fell after successful therapy but increased after relapse. In many cells high concentrations of GMP have an antiproliferative effect. The cellular cGMP extrusion from cancer cells may represent an acquired resistance against an endogenous antiproliferative signal molecule. Multidrug resistance associated protein 5 (MRP5) has been identified as an important cGMP transporter. Methods: A human erythroleukemia cell line (HEL) was used to study the impact of cGMP and cGMP-elevating compounds like theophylline, sodium nitroprusside (SNP) and sodium nitrite (NaNO2). MRP5 was overexpressed in HEL cells by transfection. Concentrations of cGMP were determined with RIA or HPLC and cell densities were determined by cytometry. Results: The concentration ratio between extra- and intracellular cGMP concentrations was >1, meaning that HEL cells extruded cGMP against a concentration gradient and MRP5 was identified in these cells. In some cell types butyrate increases cellular cGMP levels by stimulating soluble guanylyl cyclase (sGC) and thereby the cellular efflux. This effect did not exist for HEL cells. MRP5 transfected HEL cells which were exposed to cGMP was clearly more sensitive to the antiproliferative effect than the wild type. On the other hand, exposing the transfected HEL cells to cGMP-elevating agents (theophylline, SNP and NaNO<sub>2</sub>) showed less sensitivity than the wildtype. Conclusion: This study supports the idea that some cancers acquire resistance against endogenous signal molecules with antiproliferative potency.展开更多
Nucleotide second messengers are highly versatile signaling molecules that regulate a variety of key biological processes in bacteria.The best-studied examples are cyclic AMP(cAMP)and bis-(3'-5')-cyclic dimeri...Nucleotide second messengers are highly versatile signaling molecules that regulate a variety of key biological processes in bacteria.The best-studied examples are cyclic AMP(cAMP)and bis-(3'-5')-cyclic dimeric guanosine monophosphate(c-di-GMP),which both act as global regulators.Global regulatory frameworks of c-di-GMP and cAMP in bacteria show several parallels but also significant variances.In this review,we llustrate the global regulatory models of the two nucleotide second messengers,compare the different regulatory frameworks between c-di-GMP and cAMP,and discuss the mechanisms and physiological significance of cross-regulation between c-di-GMP and cAMP.c-di-GMP responds to numerous signals de-pendent on a great number of metabolic enzymes,and it regulates various signal transduction pathways through its huge number of effectors with varying activities.In contrast,due to the limited quantity,the cAMP metabolic enzymes and its major effector are regulated at different levels by diverse signals.cAMP performs its global regulatory function primarily by controlling the transcription of a large number of genes via cAMP receptor protein(CRP)in most bacteria.This review can help us understand how bacteria use the two typical nucleotide second messengers to effectively coordinate and integrate various physiological processes,providing theoretical guidelines for future research.展开更多
文摘Background: Previous studies of patients with acute leukemia showed that plasma cGMP levels were markedly elevated before treatment, fell after successful therapy but increased after relapse. In many cells high concentrations of GMP have an antiproliferative effect. The cellular cGMP extrusion from cancer cells may represent an acquired resistance against an endogenous antiproliferative signal molecule. Multidrug resistance associated protein 5 (MRP5) has been identified as an important cGMP transporter. Methods: A human erythroleukemia cell line (HEL) was used to study the impact of cGMP and cGMP-elevating compounds like theophylline, sodium nitroprusside (SNP) and sodium nitrite (NaNO2). MRP5 was overexpressed in HEL cells by transfection. Concentrations of cGMP were determined with RIA or HPLC and cell densities were determined by cytometry. Results: The concentration ratio between extra- and intracellular cGMP concentrations was >1, meaning that HEL cells extruded cGMP against a concentration gradient and MRP5 was identified in these cells. In some cell types butyrate increases cellular cGMP levels by stimulating soluble guanylyl cyclase (sGC) and thereby the cellular efflux. This effect did not exist for HEL cells. MRP5 transfected HEL cells which were exposed to cGMP was clearly more sensitive to the antiproliferative effect than the wild type. On the other hand, exposing the transfected HEL cells to cGMP-elevating agents (theophylline, SNP and NaNO<sub>2</sub>) showed less sensitivity than the wildtype. Conclusion: This study supports the idea that some cancers acquire resistance against endogenous signal molecules with antiproliferative potency.
基金funded by the National Natural Science Foundation of China(Nos.32370023,32370583,31970036,and 31900401)Natural Science Foundation of the Jiangsu Higher Education Institutions of China(20KJB180001 and 20KJA180007)+2 种基金Natural Science Foundation of Jiangsu Province(BK20210920 and BK20231350)Jiangsu Agricultural Science and Technology Innovation Fund(Cx223125)Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘Nucleotide second messengers are highly versatile signaling molecules that regulate a variety of key biological processes in bacteria.The best-studied examples are cyclic AMP(cAMP)and bis-(3'-5')-cyclic dimeric guanosine monophosphate(c-di-GMP),which both act as global regulators.Global regulatory frameworks of c-di-GMP and cAMP in bacteria show several parallels but also significant variances.In this review,we llustrate the global regulatory models of the two nucleotide second messengers,compare the different regulatory frameworks between c-di-GMP and cAMP,and discuss the mechanisms and physiological significance of cross-regulation between c-di-GMP and cAMP.c-di-GMP responds to numerous signals de-pendent on a great number of metabolic enzymes,and it regulates various signal transduction pathways through its huge number of effectors with varying activities.In contrast,due to the limited quantity,the cAMP metabolic enzymes and its major effector are regulated at different levels by diverse signals.cAMP performs its global regulatory function primarily by controlling the transcription of a large number of genes via cAMP receptor protein(CRP)in most bacteria.This review can help us understand how bacteria use the two typical nucleotide second messengers to effectively coordinate and integrate various physiological processes,providing theoretical guidelines for future research.