Hormones and nutrients often induce genetic programs via signaling pathways that interface with genespecific activators. For these experiments, pc12 cells were cotransfected with a. Magnesium ions strongly inhibited the interaction between gst creb and torc1 and this effect was reversed by lithium. Creb is a 43 kda basicleucine zipper bzip transcription factor that is expressed in most tissues and is conserved from drosophila to humans. Activating transcription factor 1 atf1 and the closely related proteins creb cyclic amp resonse element binding protein and crem cyclic amp response element modulator constitute a subfamily of bzip transcription factors. The cellular mechanism forper1 elevation and light induced. Radiation therapy is a firstline treatment for prostate cancer patients with localized tumors. While changes in gene expression are critical for many brain functions, including longterm memory, little is known about the cellular processes that mediate stimulustranscription coupling at central synapses. Phosphorylated crtcs are sequestered in the cytoplasm, but rapidly dephosphorylated and translocated into the nucleus following a stressful stimulus. Aug 19, 2011 oxidative stress plays an important role in neuronal dysfunction and neuron loss in alzheimers brain. Although some patients respond well to the treatment. As creb phosphorylation is known to be a key step in coupling shortterm neuronal stimuli to longterm intracellular responses yamamoto et al. Conserved and distinct modes of crebatf transcription.
Therefore, we examined the ability of an oligodeoxynucleotide odn decoy credecoy to 1 sequester creb and inhibit cremediated transcription, 2 inhibit glu induced phase advances of scn electrical activity and light induced phase advances of wheel running activity, and 3 block glu induced upregulation of per1 levels. These studies implicate defective creb dependent plasticity in the mechanism underlying. In studying the signaling pathways by which synaptic inputs control the phosphorylation state of cyclic ampresponsive element binding protein creb. Activating transcription factor 1 atf1 and the closely related proteins creb cyclic amp resonse element binding protein and crem cyclic amp response element modulator constitute a subfamily of bzip transcription factors that play critical roles in the regulation of cellular growth, metabolism, and survival. Creb functions as a stimulusinduced transcriptional activator in organisms. Induced transcription is regulated primarily by activity at the cre, with only small contributions from the ap1 or hypoxia response element 1 hre1. Therefore, we examined the expression of creb in the hippocampal neurons of tg2576 mice, ad postmortem brain and in. Downregulation of creb expression in alzheimers brain and in. A dominantnegative inhibitor of creb reveals that it is a. Creb and its close relatives are now widely accepted as prototypical stimulusinducible transcription factors. In neurons, a wide range of extracellular stimuli are capable of activating creb family members, and crebdependent. In addition, although atm is required for the induction of the p53 transcriptional program in response to dna damage, the identities of the relevant transcription. Specificity of 66615 has been previously investigated and shown to inhibit creb s transcription activity with an ic 50 of approximately 80 to 100 nmoll. Activation of the camp pathway, for example, stimulates cellular gene expression by means of the pkamediated phosphorylation of campresponse element binding protein creb.
Direct regulation of creb transcriptional activity by atm in response. Transcription of various genes is regulated by the cyclic amp camp signal transduction pathway through a family of camp responsive element crebinding transcription factors that include creb. Tyrosine hydroxylase transcription depends primarily on. Genomewide analysis of campresponse element binding. Protein kinases and transcription factors transmit the signals from the. Il6 induces the expression of creb in vivo and in vitro.
Crebdependent regulation of gad65 transcription by bdnf. The transcription factor creb is synthesized within axons of developing drg neurons in an ngfdependent fashion and transported back to the neuronal nucleus where it influences transcription. Downstream regulatory elements contribute to cfos gene transcription. A reverse transcription quantitative polymerase chain reaction and b western blot analysis illustrating creb expression in pdlscs transfected with pcdna3. A stimulusinduced transcription factor activated by a diverse array of extracellular signals. This investigation was undertaken to determine whether cremediated activation of per1 is required for lightglu induced.
Transcription is stimulated on binding to the cre of a phosphorylated creb dimer. Altered expression and function of the transcription factor cyclic amp. Diminished creinduced plasticity is linked to memory. Creb is a novel nuclear target of pten phosphatase.
Stimulation by lithium of the interaction between the. In some cases, signaling pathways target additional sites on creb or proteins associated with creb, permitting creb to regulate distinct programs of gene. Cam kinase iv activates the transcription factor creb, and expression of a dominant negative form of creb blocks calcium and cam kinase ivinduced dendritic growth. A stimulusinduced transcription factor activated by. In many cell types, these factors function as effector molecules that bring about cellular changes in response to discrete sets of instructions.
Neuroprotective effect of arctigenin via upregulation of p. Our findings raise the possibility that pkacreb signalling may. This study was designed to reveal the role of torc1 and sirt1mediating creb target gene transcription in ltm impairment induced by al, and to hopefully provide new evidence to enlighten the probable underlying mechanism of al. Creb is expressed in all somatic cells, and many different stimuli activate creb by phosphorylation of its serine 3 s3. Stimulusinduced phosphorylation of ser3, the major regulatory. Creb tf creb, camp response elementbinding protein is a cellular transcription factor. Protein kinase d induces transcription through direct. Creb has been implicated in a number of biological functions, all of which depend on its ability to act as a stimulus induced transcription factor that can be activated by a variety of extracellular signals. In the cytoplasm, pten dephosphorylates its primary lipid substrate, phosphatidylinositol 3,4,5. One of the best characterized stimulus induced transcription factors, cyclic amp response element crebinding protein creb, activates transcription of target genes in response to a diverse array of stimuli, including peptide hormones, growth factors, and neuronal activity, that activate a variety of protein kinases including protein kinase.
Local translation and retrograde axonal transport of creb. Previous studies have reported downregulation of crebmediated transcription by oxidative stress and a the promoter for creb itself contains cyclic amp response elements. Creb was first described in 1987 as a campresponsive transcription factor regulating the somatostatin gene genes whose transcription is regulated by creb include. While changes in gene expression are critical for many brain functions, including longterm memory, little is known about the cellular processes that mediate stimulus transcription coupling at central synapses. The genes for these transcription factors encode multiple isoforms that. In this study, we explored the antiinflammatory properties of. Cyclic amp response element binding protein creb is a constitutively expressed nuclear transcription factor that regulates the expression of genes involved in neuronal survival and function. Glucose transporter glut8 translocation in neurons is not insulin responsive. Creb transcriptional activity is upregulated in response to many cellular stimuli, including. Pdf protein kinase a signaling via creb controls myogenesis. This study was designed to reveal the role of torc1 and sirt1mediating creb target gene transcription in ltm impairment induced. One of the best characterized stimulusinduced transcription factors, cyclic amp response element cre binding protein creb, activates transcription of target genes in response to a diverse array of. Function and regulation of creb family transcription factors in.
As the stress response is attenuated by oxytocin ot. Members of the creb atf subfamily of bzip transcription factors, including creb, crem, and atf1 were among the first stimulus induced transcription factors to be identified. Enhancement by lithium of campinduced crecrebdirected gene. Abnormalities of creb expression is observed in the brain of individuals.
Function and regulation of creb family transcription factors. Arc also significantly attenuated downregulation of the phosphorylation of creb p creb induced by h89, which may contribute to the neuroprotective effects of arc. Bars without a common letter differ, p induced by mll chimeric oncoproteins are among the subset of cancers distinguished by a paradoxical dependence on gsk3 kinase activity for sustained proliferation. Protein kinase a signaling via creb controls myogenesis. Selfexcising retroviral vectors encoding the cre recombinase overcome cremediated cellular toxicity. The wellknown upstream enhancer elements sre and carecre bind to transcription factors, including the ternary complex factor tcf, srf, and creb, which mediate stimulus induced transcription. Overexpression of creb protects pdlscs from h2o2 induced cytotoxicity. Ca2 camp response elementbinding protein crebdependent. Light is a prominent stimulus that synchronizes endogenous circadian rhythmicity to environmental lightdark cycles. We previously reported that high pathophysiological concentrations of leptin, the adipocytesecreted peptide, upregulate the expression of a potent proatherogenic matricellular protein, thrombospon.
Sep 02, 2015 the major regulator of the neuroendocrine stress response in the brain is corticotropin releasing factor crf, whose transcription is controlled by creb and its cofactors crtc23 torc23. We demonstrate here that gsk3 maintains the mll leukemia stem cell transcriptional program by promoting the conditional association of creb and its coactivators torc and cbp with homedomain protein meis1, a. The binding of creb and usf12 transcription factors to a proximal, overlapping creebox element is the underlying mechanism for cox2 gene expression. Overexpressing creb significantly reduced the ros levels and protein expression levels of apoptotic genes in pdlscs. Transcription factor creb is believed to play essential roles in the formation of longterm memory ltm, but not in learning and shortterm memory stm. Cells transfected with creb sirna were cultured for 36 h and starved for 24 h.
Creb is a crucial component of transcriptional enhancers that regulate functions of the developing and mature brain, including in neuronal survival, synaptogenesis, synaptic plasticity and drug addiction 22, 24 26. A cluster of phosphorylation sites on the cyclic ampregulated nuclear factor creb. The camp response element binding protein creb is a nuclear factor that is regulated by protein kinase a phosphorylation. Regulation of osteoclast differentiation and function by. As a transcription factor, activated creb regulates transcription of an array of genes that harbor the creb binding sites in their promoter proximal region, including those with survival function 6 x 6.
Creb not only mediates stimulus transcription coupling of the camp signaling pathway but functions as a point of convergence of many other signaling molecules involving calcium, neurotrophins, tumor promoters, and growth factors. Taken together, these functions of kid and cad lead to a simple and oftdescribed model of stimulus induced creb mediated transcription. These results demonstrated that arc exerted the ability to protect neurons and shsy5y cells against h89 induced cell injury via upregulation of p creb. Doninduced il6 gene transcription but not il6 mrna stability is suppressed in peritoneal macrophages from dhafed mice. Conserved and distinct modes of crebatf transcription factor.
The phosphorylation of the erk pathway is indispensable in the activation of creb induced. Creb is essential for the formation and retention of memory in several species 4, 5. Lysophosphatidic acid lpa, a naturally occurring bioactive phospholipid, activates g proteincoupled receptors gpcrs, leading to regulation of diverse cellular events including cell survival and apoptosis. Since creb is a major mediator of neuronal neurotrophic response in other cellular contexts bonni et al. One of the best characterized stimulus induced transcription factors, cyclic amp response element cre binding protein creb, activates transcription of target genes in response to a diverse array of stimuli. As their therapeutic action requires chronic treatment, adaptive neuronal processes are suggested to be involved. Crebdependent regulation of gad65 transcription by bdnftrkb. This investigation was undertaken to determine whether cremediated activation of per1 is required for lightgluinduced phase resetting of the scn clock. Since creb contributes to ngf induced transcription of cfos and since many other ngf induced genes contain putative creb binding sites, we investigated the role of creb in ngf induction of the morphological differentiation of pc12 cells fig. American journal of respiratory and critical care medicine. Crecrebdriven upregulation of gene expression by chronic. The molecular mechanism of the action of lithium salts in the treatment of bipolar disorder is not well understood. Despite extensive studies of the signaling pathways that mediate lparegulated cell growth and survival, the mechanisms underlying the apoptotic effect of lpa remain largely unclear. Transcription of various genes is regulated by the cyclic amp camp signal transduction pathway through a family of c amp r esponsive e lement creb inding transcription factors that include creb, crem cre m odulator, and atf1 a ctivating t ranscription f actor 1.
Creb is a 43kda transcription factor whose activity is regulated by phosphorylation. Calcium regulation of neuronal gene expression pnas. The phosphorylationdependent activation of a further creb family transcription factor, atf2, was also assessed, but did not show any significant hypoxia induced alterations data not shown. In studying the signaling pathways by which synaptic inputs control the phosphorylation state of cyclic ampresponsive element binding protein creb and determine expression of cre.
Creb phosphorylation initiates the recruitment of creb interacting proteins to the cres present in creb target genes shaywitz and greenberg 1999, promoting transcription. For il6 mrna a and hnrna b expression, macrophages were cultured with don 250. Interestingly, both creb and crem encode transcription factors that. One target gene of creb is the transcription factor cfos. Exposure to dna damage further induced atf1 phosphorylation on. Tobacco carcinogeninduced production of gmcsf activates. Function and regulation of creb family transcription. Johannessen cm et al 20 a melanocyte lineage program confers. Although one function of creb in neurons is believed to be the regulation of genes whose products control synaptic function, the targets of creb. The present results demonstrated that the expression of creb was reduced in a dosedependent manner in response to the h 2 o 2 stimulus.
The canonical creb activation pathway involves stimulusinduced. The major regulator of the neuroendocrine stress response in the brain is corticotropin releasing factor crf, whose transcription is controlled by creb and its cofactors crtc23. Ionizing radiation induces prostate cancer neuroendocrine. Clone rea1 recognizes the serine 3 s3phosphorylated form of the human camp responsive element crebinding transcription factor creb, a member of a family of camp responsive element crebinding transcription factors that include creb, cre modulator crem, and activating transcription. However, the molecular mechanisms underlying tumor recurrence remain largely unknown. Protein kinase a signaling via creb controls myogenesis induced by wnt genes article pdf available in nature 4337023. Creb mediates erkinduced survival of mouse renal tubular. Role of camp response element binding protein in cardiovascular. Creb is a major transcription factor that mediates activitydependent gene transcription across a wide variety of cell types. Magnesium ions strongly inhibited the interaction between gstcreb and torc1 and this effect was reversed by lithium.
Oxytocin regulates stressinduced crf gene transcription. Since creb contributes to ngfinduced transcription of cfos and since many other ngfinduced genes contain putative creb binding sites, we investigated the role of creb in ngf induction of the morphological differentiation of pc12 cells fig. Wnt proteins can also stimulate crebmediated transcription, providing evidence for a wnt signalling pathway involving pka and creb. Docosahexaenoic acid consumption inhibits deoxynivalenol. Hypoxic adaptation engages the cbpcrestinduced coactivator. Creb phosphorylation, but the role of other regulatory factors in al induced ltm impairment is still obscure. Pten phosphatase is a potent tumor suppressor that regulates multiple cellular functions. Creb is a transcription factor which binds to dna and increases expression of antiinflammatory genes 11. Nsaids potently suppressed the proliferations and may offer a novel approach for chemoprevention and therapy of gepnets. The transcriptional activity and specificity of creb are regulated by the signaling.
Downregulation of creb expression in alzheimers brain and. Nocturnal light elevates mrna of the period1per1 gene and induces long term state changes, expressed as phase shifts of circadian rhythms. Creb is a transcription factor implicated in the control of adaptive neuronal responses. Creb binds to the octanucleotide camp response element cre tganntca as a homodimer and as heterodimers in conjunction with other members of the creb. The authors link cfos expression to stress induced gene transcription. Impairments in learning induced activation of creb in these mice are manifested by reduced credriven gene transcription. Enhancement by lithium of campinduced crecrebdirected. Thus our results suggest that, once torc has entered the nucleus, lithium as a cation stimulates directly the binding of torc to creb, leading to an increase in camp induced creb targetgene transcription. The cyclic amp response element binding protein1 creb 1 or simply creb is a nuclear factor that mediates stimulus induced transcription in the nucleus.
Lysophosphatidic acid triggers apoptosis in hela cells. The authors link cfos expression to stress induced gene transcription and neuroplasticity. Thus our results suggest that, once torc has entered the nucleus, lithium as a cation stimulates directly the binding of torc to creb, leading to an increase in campinduced creb targetgene transcription. Creb is a ubiquitous transcription factor that controls cell proliferation and survival. A stimulus induced transcription factor activated by a diverse array of extracellular signals vol 68, pg 821, 1999 extracellular stimuli elicit changes in gene. Extracellular stimuli elicit changes in gene expression in target cells by activating intracellular protein kinase cascades that phosphorylate transcription factors within the nucleus. A stimulusinduced transcription factor activated by a.
Creb was first described in 1987 as a camp responsive transcription factor regulating the somatostatin gene. To further delineate the role of creb in nnk induced pancreatic carcinogenesis, miapaca2 cells were treated with a creb inhibitor crebi, 66615 with or without nnk exposure. Interestingly, there were no significant changes in creb or atf1 phosphorylation in three systemic organs kidney, liver, and spleen isolated from the. The camp response element binding protein creb is a ubiquitously expressed nuclear transcription factor that is activated by various extracellular stimuli. It binds to certain dna sequences called camp response elements cre, thereby increasing or decreasing the transcription of the genes. Here we show that fractionated ionizing radiation ir.
1392 140 743 303 1090 1259 976 627 151 1395 405 715 1519 433 228 343 1138 1291 1106 169 985 1000 189 720 1125 903 1006 1309 805 672 361 635 865 1029 803 205 204 247