This paper reviews the distinctive roles played by the transcriptional coactivators CREB-binding protein(CBP) and p300 in Wnt/β-catenin signaling and cell physiology in colorectal cancer(CRC). Specifically, we focus ...This paper reviews the distinctive roles played by the transcriptional coactivators CREB-binding protein(CBP) and p300 in Wnt/β-catenin signaling and cell physiology in colorectal cancer(CRC). Specifically, we focus on the effects of CBP- and p300-mediated Wnt activity on(1) neoplastic progression;(2) the activities of butyrate, a breakdown product of dietary fiber, on cell signaling and colonic cell physiology;(3) the development of resistance to histone deacetylase inhibitors(HDACis), including butyrate and synthetic HDACis, in colonic cells; and(4) the physiology and number of cancer stem cells. Mutations of the Wnt/β-catenin signaling pathway initiate the majority of CRC cases, and we have shown that hyperactivation of this pathway by butyrate and other HDACis promotes CRC cell apoptosis. This activity by butyrate may in part explain the preventive action of fiber against CRC. However, individuals with a high-fiber diet may still develop neoplasia; therefore, resistance to the chemopreventive action of butyrate likely contributes to CRC. CBP or p300 may modify the ability of butyrate to influence colonic cell physiology since the two transcriptional coactivators affect Wnt signaling, and likely, its hyperactivation by butyrate. Also, CBP and p300 likely affect colonic tumorigenesis, as well as stem cell pluripotency. Improvement of CRC prevention and therapy requires a better understanding of the alterations in Wnt signaling and gene expression that underlie neoplastic progression, stem cell fate, and the development of resistance to butyrate and clinically relevant HDACis. Detailed knowledge of how CBP- and p300 modulate colonic cell physiology may lead to new approaches for anti-CRC prevention and therapeutics, particularly with respect to combinatorial therapy of CBP/p300 inhibitors with HDACis.展开更多
BACKGROUND Angiomatoid fibrous histiocytoma(AFH)is a rare,slow-growing soft tissue tumor.It appears mostly on the limbs and trunk in children and young adults.The biology of AFH remains unclear because of the small nu...BACKGROUND Angiomatoid fibrous histiocytoma(AFH)is a rare,slow-growing soft tissue tumor.It appears mostly on the limbs and trunk in children and young adults.The biology of AFH remains unclear because of the small number of reported cases.Diagnostic testing does not provide definitive results.It has two clinical forms,that differ in terms of gene expression and clinical prognosis.It is important to inform the laboratory which specific gene testing is necessary.Here,we describe a case of rare AFH in the submandibular region using a full genetic panel.CASE SUMMARY A 13-year-old boy who had been misdiagnosed in the past 6 mo by his dentist visited our clinic because of a lesion in the submandibular area on the right side.The lesion was homogeneous and painless upon palpation.No skin discoloration was observed.Due to the non-specific radiological picture computed tomography(CT),magnetic resonance imaging(MRI),cone-beam CT(CBCT),and ultrasoundguided biopsy were performed.A venous malformation was suspected on the MRI.None of the tests provided a definitive diagnosis.Owing to the non-specific radiological findings,the patient qualified for surgical treatment.The surgical procedure included an excisional biopsy.The diagnostic testing was extended using gene rearrangements.The most distinctive gene translocation in diagnosing AFH is within the EWS RNA-binding protein 1(EWSR1)-CREB-binding protein.However,in this case,the diagnosis was confirmed by a rearrangement within the EWSR1 gene testing.CONCLUSION AFH in the submandibular location is rare,and surgical treatment with genetic evaluation defines AFH type that affects subsequent procedures.展开更多
Environmental enrichment is known to be beneficial for cognitive improvement.In many animal models of neurological disorders and brain injury,EE has also demonstrated neuroprotective benefits in neurodegenerative dise...Environmental enrichment is known to be beneficial for cognitive improvement.In many animal models of neurological disorders and brain injury,EE has also demonstrated neuroprotective benefits in neurodegenerative diseases and in improving recovery after stroke or traumatic brain injury.The exact underlying mechanism for these phenomena has been unclear.Recent findings have now indicated that neuronal activity elicited by environmental enrichment induces Ca2+influx in dorsal root ganglion neurons results in lasting enhancement of CREB-binding protein-mediated histone acetylation.This,in turn,increases the expression of pro-regeneration genes and promotes axonal regeneration.This mechanism associated with neuronal activity elicited by environmental enrichment-mediated pathway is one of several epigenetic mechanisms which modulate axon regeneration upon injury that has recently come to light.The other prominent mechanisms,albeit not yet directly associated with environmental enrichment,include DNA methylation/demethylation and N6-methyladenosine modification of transcripts.In this brief review,I highlight recent work that has shed light on the epigenetic basis of environmental enrichment-based axon regeneration,and discuss the mechanism and pathways involved.I further speculate on the implications of the findings,in conjunction with the other epigenetic mechanisms,that could be harness to promote axon regeneration upon injury.展开更多
The thymine DNA glycosylase （TDG） is a multifunctional enzyme,which is essential for embryonic development.It mediates the base excision repair （BER） of G：T and G：U DNA mismatches arising from the deamination of...The thymine DNA glycosylase （TDG） is a multifunctional enzyme,which is essential for embryonic development.It mediates the base excision repair （BER） of G：T and G：U DNA mismatches arising from the deamination of 5-methyl cytosine （5-MeC） and cytosine,respectively.Recent studies have pointed at a role of TDG during the active demethylation of 5-MeC within CpG islands.TDG interacts with the histone acetylase CREB-binding protein （CBP） to activate CBP-dependent transcription.In addition,TDG also interacts with the retinoic acid receptor α （RARα）,resulting in the activation of RARα target genes.Here we provide evidence for the existence of a functional ternary complex containing TDG,CBP and activated RARα.Using global transcriptome profiling,we uncover a coupling of de novo methylation-sensitive and RA-dependent transcription,which coincides with a significant subset of CBP target genes.The introduction of a point mutation in TDG,which neither affects overall protein structure nor BER activity,leads to a significant loss in ternary complex stability,resulting in the deregulation of RA targets involved in cellular networks associated with DNA replication,recombination and repair.We thus demonstrate for the first time a direct coupling of TDG＇s epigenomic and transcription regulatory function through ternary complexes with CBP and RARα.展开更多
Cancers are heterogeneous at the cellular level.Cancer stem cells/tumor initiating cells(CSC/TIC)both initiate tumorigenesis and are responsible for therapeutic resistance and disease relapse.Elimination of CSC/TIC sh...Cancers are heterogeneous at the cellular level.Cancer stem cells/tumor initiating cells(CSC/TIC)both initiate tumorigenesis and are responsible for therapeutic resistance and disease relapse.Elimination of CSC/TIC should therefore be able to reverse therapy resistance.In principle,this could be accomplished by either targeting cancer stem cell surface markers or“stemness”pathways.Although the successful therapeutic elimination of“cancer stemness”is a critical goal,it is complex in that it should be achieved without depletion of or increases in somatic mutations in normal tissue stem cell populations.In this perspective,we will discuss the prospects for this goal via pharmacologically targeting differential Kat3 coactivator/Catenin usage,a fundamental transcriptional control mechanism in stem cell biology.展开更多
基金Supported by National Institutes of Health(Bethesda,MD)National Cancer Institute,No.1R15CA149589-01
文摘This paper reviews the distinctive roles played by the transcriptional coactivators CREB-binding protein(CBP) and p300 in Wnt/β-catenin signaling and cell physiology in colorectal cancer(CRC). Specifically, we focus on the effects of CBP- and p300-mediated Wnt activity on(1) neoplastic progression;(2) the activities of butyrate, a breakdown product of dietary fiber, on cell signaling and colonic cell physiology;(3) the development of resistance to histone deacetylase inhibitors(HDACis), including butyrate and synthetic HDACis, in colonic cells; and(4) the physiology and number of cancer stem cells. Mutations of the Wnt/β-catenin signaling pathway initiate the majority of CRC cases, and we have shown that hyperactivation of this pathway by butyrate and other HDACis promotes CRC cell apoptosis. This activity by butyrate may in part explain the preventive action of fiber against CRC. However, individuals with a high-fiber diet may still develop neoplasia; therefore, resistance to the chemopreventive action of butyrate likely contributes to CRC. CBP or p300 may modify the ability of butyrate to influence colonic cell physiology since the two transcriptional coactivators affect Wnt signaling, and likely, its hyperactivation by butyrate. Also, CBP and p300 likely affect colonic tumorigenesis, as well as stem cell pluripotency. Improvement of CRC prevention and therapy requires a better understanding of the alterations in Wnt signaling and gene expression that underlie neoplastic progression, stem cell fate, and the development of resistance to butyrate and clinically relevant HDACis. Detailed knowledge of how CBP- and p300 modulate colonic cell physiology may lead to new approaches for anti-CRC prevention and therapeutics, particularly with respect to combinatorial therapy of CBP/p300 inhibitors with HDACis.
文摘BACKGROUND Angiomatoid fibrous histiocytoma(AFH)is a rare,slow-growing soft tissue tumor.It appears mostly on the limbs and trunk in children and young adults.The biology of AFH remains unclear because of the small number of reported cases.Diagnostic testing does not provide definitive results.It has two clinical forms,that differ in terms of gene expression and clinical prognosis.It is important to inform the laboratory which specific gene testing is necessary.Here,we describe a case of rare AFH in the submandibular region using a full genetic panel.CASE SUMMARY A 13-year-old boy who had been misdiagnosed in the past 6 mo by his dentist visited our clinic because of a lesion in the submandibular area on the right side.The lesion was homogeneous and painless upon palpation.No skin discoloration was observed.Due to the non-specific radiological picture computed tomography(CT),magnetic resonance imaging(MRI),cone-beam CT(CBCT),and ultrasoundguided biopsy were performed.A venous malformation was suspected on the MRI.None of the tests provided a definitive diagnosis.Owing to the non-specific radiological findings,the patient qualified for surgical treatment.The surgical procedure included an excisional biopsy.The diagnostic testing was extended using gene rearrangements.The most distinctive gene translocation in diagnosing AFH is within the EWS RNA-binding protein 1(EWSR1)-CREB-binding protein.However,in this case,the diagnosis was confirmed by a rearrangement within the EWSR1 gene testing.CONCLUSION AFH in the submandibular location is rare,and surgical treatment with genetic evaluation defines AFH type that affects subsequent procedures.
基金supported by the National University of Singapore Graduate School for Integrative Sciences and Engineering(to BLT)
文摘Environmental enrichment is known to be beneficial for cognitive improvement.In many animal models of neurological disorders and brain injury,EE has also demonstrated neuroprotective benefits in neurodegenerative diseases and in improving recovery after stroke or traumatic brain injury.The exact underlying mechanism for these phenomena has been unclear.Recent findings have now indicated that neuronal activity elicited by environmental enrichment induces Ca2+influx in dorsal root ganglion neurons results in lasting enhancement of CREB-binding protein-mediated histone acetylation.This,in turn,increases the expression of pro-regeneration genes and promotes axonal regeneration.This mechanism associated with neuronal activity elicited by environmental enrichment-mediated pathway is one of several epigenetic mechanisms which modulate axon regeneration upon injury that has recently come to light.The other prominent mechanisms,albeit not yet directly associated with environmental enrichment,include DNA methylation/demethylation and N6-methyladenosine modification of transcripts.In this brief review,I highlight recent work that has shed light on the epigenetic basis of environmental enrichment-based axon regeneration,and discuss the mechanism and pathways involved.I further speculate on the implications of the findings,in conjunction with the other epigenetic mechanisms,that could be harness to promote axon regeneration upon injury.
基金funded by the Centre National de la Recherche Scientifique(CNRS)and the Genopole Evry
文摘The thymine DNA glycosylase （TDG） is a multifunctional enzyme,which is essential for embryonic development.It mediates the base excision repair （BER） of G：T and G：U DNA mismatches arising from the deamination of 5-methyl cytosine （5-MeC） and cytosine,respectively.Recent studies have pointed at a role of TDG during the active demethylation of 5-MeC within CpG islands.TDG interacts with the histone acetylase CREB-binding protein （CBP） to activate CBP-dependent transcription.In addition,TDG also interacts with the retinoic acid receptor α （RARα）,resulting in the activation of RARα target genes.Here we provide evidence for the existence of a functional ternary complex containing TDG,CBP and activated RARα.Using global transcriptome profiling,we uncover a coupling of de novo methylation-sensitive and RA-dependent transcription,which coincides with a significant subset of CBP target genes.The introduction of a point mutation in TDG,which neither affects overall protein structure nor BER activity,leads to a significant loss in ternary complex stability,resulting in the deregulation of RA targets involved in cellular networks associated with DNA replication,recombination and repair.We thus demonstrate for the first time a direct coupling of TDG＇s epigenomic and transcription regulatory function through ternary complexes with CBP and RARα.
基金Kahn M has been supported by NIH P30CA014089,R01CA166161,R21NS074392,R21AI105057,and R01HL112638Bild A has been supported by NIH U54CA209978.
文摘Cancers are heterogeneous at the cellular level.Cancer stem cells/tumor initiating cells(CSC/TIC)both initiate tumorigenesis and are responsible for therapeutic resistance and disease relapse.Elimination of CSC/TIC should therefore be able to reverse therapy resistance.In principle,this could be accomplished by either targeting cancer stem cell surface markers or“stemness”pathways.Although the successful therapeutic elimination of“cancer stemness”is a critical goal,it is complex in that it should be achieved without depletion of or increases in somatic mutations in normal tissue stem cell populations.In this perspective,we will discuss the prospects for this goal via pharmacologically targeting differential Kat3 coactivator/Catenin usage,a fundamental transcriptional control mechanism in stem cell biology.
