Intracellular K～+ Selectively Regulates the DNA Binding Activities of Transcription Factors to Control Neuronal Survival
|School||Shanghai Institutes for Biological Sciences|
|Keywords||neuronal apoptosis transcription factor NF-κB p53 Forkhead CREB intracellular potassium concentration DNA binding|
Apoptosis plays crucial roles in the normal tissue homeostasis. The molecularmechanism of apoptosis has been extensively investigated. More and more evidenceshowed that K~+ homeostasis plays an important role in apoptosis. Excessive K~+efflux and intracellular K~+ loss is a common event in apoptosis of many cell types.Recent studies demonstrated that decrease of intracellular K~+ concentration ([K~+]i) is akey step in early stage of apoptosis and low [K~+]i may serve as a death signal allowingthe execution of the suicide program. Blocking K~+ loss by K~+ channel blocker orelevating extracellular [K~+] prevents apoptosis. However, the mechanism how low[K~+]i promotes apoptosis remains unclear. Since many transcription factors have beenreported involved in neuron apoptosis, gene transcription plays important roles inapoptosis. We hypothesized that low [K~+]i might regulate the expression ofapoptotic genes through direct and selective effect on DNA binding activities of sometranscription factors to promote apoptosis.Using EMSAs we found that low [K~+] promotes DNA binding activities ofNF-κB, p53, Forkheand, HIF and Oct-1, whereas inhibited that of CREB, AP-1 andNPAS2. DNA binding activities of SP1, STAT, E2F, YY1, C/EBP and Egr-1 werenot affected by different [K~+]. Interestingly, NF-κB, p53, Forkheand and HIF arereported as proapoptotic transcription factors whereas CREB and AP1 promote cellsurvival. Using rat cortical neurons deprived of serum or treated by K~+ ionophoresas models for K~+ loss-induced apoptosis, we provide evidence that decreased [K~+]iincreased the expression of Bcl-XS, BAX and Bim, the downstream pro-apoptoticgenes of NF-κB, p53 and Forkhead respectively whereas decreased that of c-fos,Nur77 and Nor-1, the downstream genes of CREB. ChIP assays demonstrated thatin vivo NF-κB/DNA binding activity increased when [K+]i decreased in neurons. Allthese results supported the notion that [K+]i might directly and selectively affect DNAbinding of various transcription factors and regulate the expression of theirdownstream genes to promote neuronal apoptosis.