Transcriptional activator. Binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production (By similarity). It binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I. Regulates the induction of DDIT3/CHOP and asparagine synthetase (ASNS) in response to ER stress. In concert with DDIT3/CHOP, activates the transcription of TRIB3 and promotes ER stress-induced neuronal apoptosis by regulating the transcriptional induction of BBC3/PUMA.
C/EBP homology protein (CHOP), a stress-induced transcription factor, is involved in transcriptional regulation, cell cycle, and apoptosis. The present studies identified CHOP as an interacting partner of activating transcription factor (ATF) 4 in a yeast two-hybrid screen and confirmed their interaction in HEK293T cells. CHOP protein levels rose modestly and transiently during amino acid deprivation, whereas endoplasmic reticulum stress caused a much higher and sustained expression of CHOP protein. Exogenous CHOP expression enhanced the TRB3 gene induction by amino acid deprivation. Conversely, CHOP suppressed the induction of the endogenous asparagine synthetase (ASNS) gene and inhibited transcription from a reporter gene driven by the ASNS promoter following activation by ATF4 or amino acid deprivation. Short interfering RNA-mediated knockdown of CHOP further enhanced the induction of ASNS by either amino acid deprivation or endoplasmic reticulum stress. The CHOP-dependent repression of the ASNS gene required the entire CHOP protein, arguing against the possibility of simple sequestration of ATF4 by the CHOP leucine zipper domain, and chromatin immunoprecipitation analysis showed association of CHOP with the ASNS and TRB3 promoters. Interestingly, chromatin immunoprecipitation also showed that CHOP was associated with the C/EBP-ATF composite site regions of the SNAT2, VEGF, and CAT-1 genes, despite no significant effect on their expression after exogenous CHOP overexpression. Collectively, the results document that CHOP is a member of the transcription factor network that controls the stress-induced regulation of specific C/EBP-ATF-containing genes, such as ASNS.
C/EBP homologous protein (CHOP) is a stress-inducible nuclear protein that is crucial for the development of programmed cell death and regeneration; however, the regulation of its function has not been well characterized. Slbo, a Drosophila homolog of C/EBP (CCAAT/enhancer binding protein), was shown to be unstabilized by tribbles. Here, we identified TRB3 as a tribbles ortholog in humans, which associated with CHOP to suppress the CHOP-dependent transactivation. TRB3 is induced by various forms endoplasmic reticulum (ER) stress later than CHOP. Tunicamycin treatment enhanced the TRB3 promoter activity, while dominant-negative forms of CHOP suppressed the tunicamycin-induced activation. In addition, the tunicamycin response region in the TRB3 promoter contains amino-acid response elements overlapping the CHOP-binding site, and CHOP and ATF4 cooperated to activate this promoter activity. Knockdown of endogenous ATF4 or CHOP expression dramatically repressed tunicamycin-induced TRB3 induction. Furthermore, knockdown of TRB3 expression decreased ER stress-dependent cell death. These results indicate that TRB3 is a novel target of CHOP/ATF4 and downregulates its own induction by repression of CHOP/ATF4 functions, and that it is involved in CHOP-dependent cell death during ER stress.
The molecular basis of nephronophthisis, the most frequent genetic cause of renal failure in children and young adults, and its association with retinal degeneration and cerebellar vermis aplasia in Joubert syndrome are poorly understood. Using positional cloning, we here identify mutations in the gene CEP290 as causing nephronophthisis. It encodes a protein with several domains also present in CENPF, a protein involved in chromosome segregation. CEP290 (also known as NPHP6) interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation. NPHP6 is found at centrosomes and in the nucleus of renal epithelial cells in a cell cycle-dependent manner and in connecting cilia of photoreceptors. Abrogation of its function in zebrafish recapitulates the renal, retinal and cerebellar phenotypes of Joubert syndrome. Our findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.
C/EBP homology protein (CHOP), a stress-induced transcription factor, is involved in transcriptional regulation, cell cycle, and apoptosis. The present studies identified CHOP as an interacting partner of activating transcription factor (ATF) 4 in a yeast two-hybrid screen and confirmed their interaction in HEK293T cells. CHOP protein levels rose modestly and transiently during amino acid deprivation, whereas endoplasmic reticulum stress caused a much higher and sustained expression of CHOP protein. Exogenous CHOP expression enhanced the TRB3 gene induction by amino acid deprivation. Conversely, CHOP suppressed the induction of the endogenous asparagine synthetase (ASNS) gene and inhibited transcription from a reporter gene driven by the ASNS promoter following activation by ATF4 or amino acid deprivation. Short interfering RNA-mediated knockdown of CHOP further enhanced the induction of ASNS by either amino acid deprivation or endoplasmic reticulum stress. The CHOP-dependent repression of the ASNS gene required the entire CHOP protein, arguing against the possibility of simple sequestration of ATF4 by the CHOP leucine zipper domain, and chromatin immunoprecipitation analysis showed association of CHOP with the ASNS and TRB3 promoters. Interestingly, chromatin immunoprecipitation also showed that CHOP was associated with the C/EBP-ATF composite site regions of the SNAT2, VEGF, and CAT-1 genes, despite no significant effect on their expression after exogenous CHOP overexpression. Collectively, the results document that CHOP is a member of the transcription factor network that controls the stress-induced regulation of specific C/EBP-ATF-containing genes, such as ASNS.
Aberrant retinal expression of vascular endothelial growth factor (VEGF) leading to neovascularization is a central feature of age-related macular degeneration and diabetic retinopathy, two leading causes of vision loss. Oxidative stress is suggested to occur in retinal tissue during age-related macular degeneration and diabetic retinopathy and is suspected in the mechanism of VEGF expression in these diseases. Arsenite, a thiol-reactive oxidative stressor, induces VEGF expression by a HIF-1alpha-independent mechanism. Previously, we demonstrated that homocysteine, an endoplasmic reticulum stressor, increases VEGF transcription by a mechanism dependent upon activating transcription factor ATF4. Because ATF4 is expressed in response to oxidative stress, we hypothesized that ATF4 was also responsible for increased VEGF transcription in response to arsenite. We now show that arsenite increased steady state levels of VEGF mRNA and activated transcription from a VEGF promoter construct. Arsenite induced eIF2alpha phosphorylation, resulting in increased ATF4 protein levels. Inactivation or loss of ATF4 greatly diminished the VEGF response to arsenite treatment. Overexpression of ATF4 was sufficient to activate the VEGF promoter, and arsenite cooperated with exogenous ATF4 to further activate the promoter. A complex containing ATF4 binds a DNA element at +1767 bp relative to the VEGF transcription start site, and DNA binding activity is increased by arsenite treatment. In addition, the ability of a thiol antioxidant, N-acetylcysteine, to inhibit the effect of arsenite on VEGF expression coincided with its ability to inhibit phosphorylation of eIF2alpha and ATF4 protein expression. Thus, arsenite-induced up-regulation of VEGF gene transcription occurs by an ATF4-dependent mechanism.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionUniProtKB
Regions of hypoxia are a hallmark of solid tumors. Tumor cells modulate the regulation of specific genes allowing adaptation and survival in the harsh hypoxic environment. We have identified SKIP3, a novel human kinase-like gene, which is overexpressed in multiple human tumors and is regulated by hypoxia. SKIP3 is an ortholog of the Drosophila tribbles, rat NIPK, dog C5FW, and human C8FW genes. Drosophila tribbles is involved in slowing cell-cycle progression during Drosophila development, but little is known regarding the function or tissue distribution of the vertebrate orthologs. We show that the normal tissue expression of SKIP3 is confined to human liver, while multiple primary human lung, colon, and breast tumors express high levels of SKIP3 transcript. Endogenous SKIP3 protein accumulates within 48 h under hypoxic growth conditions in HT-29 and PC-3 cells, with upregulation of the SKIP3 mRNA transcript by 72 h. We identified activating transcription factor 4 (ATF4) as a SKIP3-binding partner using the yeast-two-hybrid assay. Coexpression of SKIP3 and ATF4 showed that SKIP3 is associated with the proteolysis of ATF4, which can be blocked using a proteosome inhibitor. These results indicate that SKIP3 may be an important participant in tumor cell growth.
Evidence
2:
Inferred from Physical InteractionHGNC
The molecular basis of nephronophthisis, the most frequent genetic cause of renal failure in children and young adults, and its association with retinal degeneration and cerebellar vermis aplasia in Joubert syndrome are poorly understood. Using positional cloning, we here identify mutations in the gene CEP290 as causing nephronophthisis. It encodes a protein with several domains also present in CENPF, a protein involved in chromosome segregation. CEP290 (also known as NPHP6) interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation. NPHP6 is found at centrosomes and in the nucleus of renal epithelial cells in a cell cycle-dependent manner and in connecting cilia of photoreceptors. Abrogation of its function in zebrafish recapitulates the renal, retinal and cerebellar phenotypes of Joubert syndrome. Our findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.
Evidence
3:
Inferred from Physical InteractionIntAct
Disrupted-In-Schizophrenia 1 (DISC1) is a novel gene associated with schizophrenia by multiple genetic studies. In order to determine how mutations in DISC1 might cause susceptibility to schizophrenia, we undertook a comprehensive study of the cellular biology of DISC1 in its full-length and disease-associated mutant forms. DISC1 interacts by yeast two-hybrid, mammalian two-hybrid, and co-immunoprecipitation assays with multiple proteins of the centrosome and cytoskeletal system, including MIPT3, MAP1A and NUDEL; proteins which localize receptors to membranes, including alpha-actinin2 and beta4-spectrin; and proteins which transduce signals from membrane receptors, including ATF4 and ATF5. Truncated mutant DISC1 fails to interact with ATF4, ATF5 or NUDEL. Deletion mapping demonstrated that DISC1 has distinct interaction domains: MAP1A interacts via its LC2 domain with the N-terminus of DISC1, whereas MIPT3 and NUDEL bind via their C-terminal domains to the central coiled-coil domain of DISC1, and ATF4/5 bind via their C-terminal domains to the C-terminus of DISC1. In its full-length form, DISC1 protein localizes to predominantly perinuclear punctate structures which extend into neurites in some cells; mutant truncated DISC1, by contrast, is seen in a diffuse pattern throughout the cytoplasm and abundantly in neurites. Both forms co-localize with the centrosomal complex, although truncated less abundantly than full-length DISC1. Although both full-length and mutant DISC1 are found in microtubule fractions, neither form of DISC1 appears to bind directly to microtubules, but rather do so in a MIPT3-dependent fashion that is stabilized by taxol. Based on these data, we propose that DISC1 is a multifunctional protein whose truncation contributes to schizophrenia susceptibility by disrupting intracellular transport, neurite architecture and/or neuronal migration, all of which have been hypothesized to be pathogenic in the schizophrenic brain.
Evidence
4:
Inferred from Physical InteractionUniProtKB
C/EBP homology protein (CHOP), a stress-induced transcription factor, is involved in transcriptional regulation, cell cycle, and apoptosis. The present studies identified CHOP as an interacting partner of activating transcription factor (ATF) 4 in a yeast two-hybrid screen and confirmed their interaction in HEK293T cells. CHOP protein levels rose modestly and transiently during amino acid deprivation, whereas endoplasmic reticulum stress caused a much higher and sustained expression of CHOP protein. Exogenous CHOP expression enhanced the TRB3 gene induction by amino acid deprivation. Conversely, CHOP suppressed the induction of the endogenous asparagine synthetase (ASNS) gene and inhibited transcription from a reporter gene driven by the ASNS promoter following activation by ATF4 or amino acid deprivation. Short interfering RNA-mediated knockdown of CHOP further enhanced the induction of ASNS by either amino acid deprivation or endoplasmic reticulum stress. The CHOP-dependent repression of the ASNS gene required the entire CHOP protein, arguing against the possibility of simple sequestration of ATF4 by the CHOP leucine zipper domain, and chromatin immunoprecipitation analysis showed association of CHOP with the ASNS and TRB3 promoters. Interestingly, chromatin immunoprecipitation also showed that CHOP was associated with the C/EBP-ATF composite site regions of the SNAT2, VEGF, and CAT-1 genes, despite no significant effect on their expression after exogenous CHOP overexpression. Collectively, the results document that CHOP is a member of the transcription factor network that controls the stress-induced regulation of specific C/EBP-ATF-containing genes, such as ASNS.
Evidence
5:
Inferred from Physical InteractionUniProtKB
Mitosin/CENP-F is a human nuclear matrix protein with multiple leucine zipper motifs. Its accumulation in S-G2 phases and transient kinetochore localization in mitosis suggest a multifunctional protein for cell proliferation. Moreover, its murine and avian orthologs are implicated in myocyte differentiation. Here we report its interaction with activating transcription factor-4 (ATF4), a ubiquitous basic leucine zipper transcription factor important for proliferation, differentiation, and stress response. The C-terminal portion of mitosin between residues 2488 and 3113 bound to ATF4 through two distinct domains, one of which was a leucine zipper motif. Mitosin mutants containing these domains were able to either supershift or disrupt the ATF4-DNA complex. On the other hand, ATF4, but not ATF1-3 or ATF6, interacted with mitosin through a region containing the basic leucine zipper motif. Moreover, overexpression of full-length mitosin repressed the transactivation activity of ATF4 in dual luciferase-based reporter assays, while knocking down mitosin expression manifested the opposite effects. These findings suggest mitosin to be a negative regulator of ATF4 in interphase through direct interaction.
Interacting selectively and non-covalently with a protein C-terminus, the end of any peptide chain at which the 1-carboxy function of a constituent amino acid is not attached in peptide linkage to another amino-acid residue.
Interacting selectively and non-covalently with DNA of a specific nucleotide composition, e.g. GC-rich DNA binding, or with a specific sequence motif or type of DNA e.g. promotor binding or rDNA binding.
Interacting selectively and non-covalently with a specific DNA sequence in order to modulate transcription. The transcription factor may or may not also interact selectively with a protein or macromolecular complex.
Multiple intracellular stress pathways converge on a single event--phosphorylation of the translation initiation factor eIF2alpha and subsequent translational activation of the transcription factor ATF4. Exploring the consequences of this event has highlighted the ways in which stress is sensed and responded to via many distinct pathways.
Multiple intracellular stress pathways converge on a single event--phosphorylation of the translation initiation factor eIF2alpha and subsequent translational activation of the transcription factor ATF4. Exploring the consequences of this event has highlighted the ways in which stress is sensed and responded to via many distinct pathways.
The series of molecular signals generated by the binding of gamma-aminobutyric acid (GABA, 4-aminobutyrate), an amino acid which acts as a neurotransmitter in some organisms, to a cell surface receptor.
The formation of glucose from noncarbohydrate precursors, such as pyruvate, amino acids and glycerol.
ISSOrtholog Curator
Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stressdefinition[GO:0070059]
A series of molecular signals in which an intracellular signal is conveyed to trigger the apoptotic death of a cell. The pathway is induced in response to a stimulus indicating endoplasmic reticulum (ER) stress, and ends when the execution phase of apoptosis is triggered. ER stress usually results from the accumulation of unfolded or misfolded proteins in the ER lumen.
Any process that stops, prevents, or reduces the frequency, rate or extent of the directed movement of potassium ions (K+) into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore.
Aberrant retinal expression of vascular endothelial growth factor (VEGF) leading to neovascularization is a central feature of age-related macular degeneration and diabetic retinopathy, two leading causes of vision loss. Oxidative stress is suggested to occur in retinal tissue during age-related macular degeneration and diabetic retinopathy and is suspected in the mechanism of VEGF expression in these diseases. Arsenite, a thiol-reactive oxidative stressor, induces VEGF expression by a HIF-1alpha-independent mechanism. Previously, we demonstrated that homocysteine, an endoplasmic reticulum stressor, increases VEGF transcription by a mechanism dependent upon activating transcription factor ATF4. Because ATF4 is expressed in response to oxidative stress, we hypothesized that ATF4 was also responsible for increased VEGF transcription in response to arsenite. We now show that arsenite increased steady state levels of VEGF mRNA and activated transcription from a VEGF promoter construct. Arsenite induced eIF2alpha phosphorylation, resulting in increased ATF4 protein levels. Inactivation or loss of ATF4 greatly diminished the VEGF response to arsenite treatment. Overexpression of ATF4 was sufficient to activate the VEGF promoter, and arsenite cooperated with exogenous ATF4 to further activate the promoter. A complex containing ATF4 binds a DNA element at +1767 bp relative to the VEGF transcription start site, and DNA binding activity is increased by arsenite treatment. In addition, the ability of a thiol antioxidant, N-acetylcysteine, to inhibit the effect of arsenite on VEGF expression coincided with its ability to inhibit phosphorylation of eIF2alpha and ATF4 protein expression. Thus, arsenite-induced up-regulation of VEGF gene transcription occurs by an ATF4-dependent mechanism.
Transcription from the asparagine synthetase (A.S.) gene is increased in response to either amino acid (amino acid response) or glucose (endoplasmic reticulum stress response) deprivation. These two independent pathways converge on the same set of genomic cis-elements within the A.S. promoter referred to as nutrient-sensing response elements (NSRE) 1 and 2, both of which are necessary for gene activation. The NSRE-1 sequence was used to screen ATF/CREB family members by electrophoresis mobility shift assays and supershift by specific antibodies. The results indicated that ATF4 binds to the NSRE-1 sequence and that the amount of the ATF4 complex was increased when extracts from amino acid-deprived or glucose-deprived cells were tested. Using electrophoresis mobility shift assay experiments and a probe that contained both NSRE-1 and NSRE-2, mutation of the NSRE-1 sequence completely prevented formation of the ATF4-containing complexes, whereas mutation of the NSRE-2 sequence did not. Overexpression of ATF4 increased A.S. promoter-driven transcription, whereas an inhibitory dominant negative ATF4 mutant blocked both basal and starvation-enhanced transcription. Collectively, the results provide both in vitro and in vivo evidence for a role of ATF4 in the transcriptional activation of the A.S. gene in response to nutrient deprivation.
The Tax protein of the Human T-cell Leukemia Virus (HTLV) activates the expression of viral mRNA through a three 21 bp repeat enhancer located within the HTLV-1 LTR. Since Tax does not bind to the 21 bp DNA repeats directly, it has been speculated that Tax interacts with cellular protein(s) which mediate binding to the enhancer. We employed the yeast two hybrid system to identify host proteins that are potentially relevant to Tax transactivation. We identified a Tax binding protein encoded from a cDNA expression library derived from peripheral blood lymphocytes. The corresponding cDNA has sequence identity with a known transcription factor, activating factor-4 (ATF-4). ATF-4 also binds to GST-Tax fusion protein in vitro. Tax mutants that did not transactivate the HTLV-1 LTR also failed to bind ATF-4. The critical domain for Tax binding resides in a 85 amino acid stretch in the C-terminus of ATF-4, which contains the basic domain and leucine zipper. We further demonstrated that both full length and N-terminal truncated ATF-4 were able to enhance Tax transactivation. Thus, ATF-4 may act as an adapter between Tax and the TRE (Tax responsive element), and play an important role in Tax-mediated transactivation.
C/EBP homologous protein (CHOP) is a stress-inducible nuclear protein that is crucial for the development of programmed cell death and regeneration; however, the regulation of its function has not been well characterized. Slbo, a Drosophila homolog of C/EBP (CCAAT/enhancer binding protein), was shown to be unstabilized by tribbles. Here, we identified TRB3 as a tribbles ortholog in humans, which associated with CHOP to suppress the CHOP-dependent transactivation. TRB3 is induced by various forms endoplasmic reticulum (ER) stress later than CHOP. Tunicamycin treatment enhanced the TRB3 promoter activity, while dominant-negative forms of CHOP suppressed the tunicamycin-induced activation. In addition, the tunicamycin response region in the TRB3 promoter contains amino-acid response elements overlapping the CHOP-binding site, and CHOP and ATF4 cooperated to activate this promoter activity. Knockdown of endogenous ATF4 or CHOP expression dramatically repressed tunicamycin-induced TRB3 induction. Furthermore, knockdown of TRB3 expression decreased ER stress-dependent cell death. These results indicate that TRB3 is a novel target of CHOP/ATF4 and downregulates its own induction by repression of CHOP/ATF4 functions, and that it is involved in CHOP-dependent cell death during ER stress.
C/EBP homology protein (CHOP), a stress-induced transcription factor, is involved in transcriptional regulation, cell cycle, and apoptosis. The present studies identified CHOP as an interacting partner of activating transcription factor (ATF) 4 in a yeast two-hybrid screen and confirmed their interaction in HEK293T cells. CHOP protein levels rose modestly and transiently during amino acid deprivation, whereas endoplasmic reticulum stress caused a much higher and sustained expression of CHOP protein. Exogenous CHOP expression enhanced the TRB3 gene induction by amino acid deprivation. Conversely, CHOP suppressed the induction of the endogenous asparagine synthetase (ASNS) gene and inhibited transcription from a reporter gene driven by the ASNS promoter following activation by ATF4 or amino acid deprivation. Short interfering RNA-mediated knockdown of CHOP further enhanced the induction of ASNS by either amino acid deprivation or endoplasmic reticulum stress. The CHOP-dependent repression of the ASNS gene required the entire CHOP protein, arguing against the possibility of simple sequestration of ATF4 by the CHOP leucine zipper domain, and chromatin immunoprecipitation analysis showed association of CHOP with the ASNS and TRB3 promoters. Interestingly, chromatin immunoprecipitation also showed that CHOP was associated with the C/EBP-ATF composite site regions of the SNAT2, VEGF, and CAT-1 genes, despite no significant effect on their expression after exogenous CHOP overexpression. Collectively, the results document that CHOP is a member of the transcription factor network that controls the stress-induced regulation of specific C/EBP-ATF-containing genes, such as ASNS.
Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating endoplasmic reticulum (ER) stress. ER stress usually results from the accumulation of unfolded or misfolded proteins in the ER lumen.
Among the new players at the endoplasmic reticulum (ER)-mitochondria interface regulating interorganelle calcium signaling, those specifically involved during ER stress are not known at present. We report here that the truncated variant of the sarcoendoplasmic reticulum Ca(2+)-ATPase 1 (S1T) amplifies ER stress through the PERK-eIF2alpha-ATF4-CHOP pathway. S1T, which is localized in the ER-mitochondria microdomains, determines ER Ca(2+) depletion due to increased Ca(2+) leak, an increased number of ER-mitochondria contact sites, and inhibition of mitochondria movements. This leads to increased Ca(2+) transfer to mitochondria in both resting and stimulated conditions and activation of the mitochondrial apoptotic pathway. Interestingly, S1T knockdown was shown to prevent ER stress, mitochondrial Ca(2+) overload, and subsequent apoptosis. Thus, by bridging ER stress to apoptosis through increased ER-mitochondria Ca(2+) transfer, S1T acts as an essential determinant of cellular fate.
The synthesis of RNA from a DNA template by RNA polymerase II, originating at an RNA polymerase II promoter. Includes transcription of messenger RNA (mRNA) and certain small nuclear RNAs (snRNAs).
ISSOrtholog Curator
Pathways
According to KEGG, this protein belongs to the following pathways:
Protein involved in the transfer of genetic information from DNA to messenger RNA (mRNA) by DNA-directed RNA polymerase. In the case of some RNA viruses, protein involved in the transfer of genetic information from RNA to messenger RNA (mRNA) by RNA-directed RNA polymerase.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
My favorites 
My labels 
Login
