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Article: Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy.

Shangary, Sanjeev / Wang, Shaomeng

Annual review of pharmacology and toxicology

2009 Volume 49, Page(s) 223–241

Abstract: Tumor suppressor p53 is an attractive cancer therapeutic target because it can be functionally activated to eradicate tumors. Direct gene alterations in p53 or interaction between p53 and MDM2 proteins are two alternative mechanisms for the inactivation ... ...

Abstract	Tumor suppressor p53 is an attractive cancer therapeutic target because it can be functionally activated to eradicate tumors. Direct gene alterations in p53 or interaction between p53 and MDM2 proteins are two alternative mechanisms for the inactivation of p53 function. Designing small molecules to block the MDM2-p53 interaction and reactivate the p53 function is a promising therapeutic strategy for the treatment of cancers retaining wild-type p53. This review will highlight recent advances in the design and development of small-molecule inhibitors of the MDM2-p53 interaction as new cancer therapies. A number of these small-molecule inhibitors, such as analogs of MI-219 and Nutlin-3, have progressed to advanced preclinical development or early phase clinical trials.
MeSH term(s)	Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Clinical Trials as Topic ; Drug Design ; Drug Evaluation, Preclinical ; Humans ; Imidazoles/chemistry ; Imidazoles/pharmacology ; Imidazoles/therapeutic use ; Neoplasms/drug therapy ; Nuclear Proteins/antagonists & inhibitors ; Piperazines/chemistry ; Piperazines/pharmacology ; Piperazines/therapeutic use ; Proto-Oncogene Proteins/antagonists & inhibitors ; Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors ; Tumor Suppressor Protein p53/chemistry ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Antineoplastic Agents ; Imidazoles ; MDM4 protein, human ; Nuclear Proteins ; Piperazines ; Proto-Oncogene Proteins ; Tumor Suppressor Protein p53 ; nutlin 3 (53IA0V845C) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2009
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	196587-6
ISSN	1545-4304 ; 0362-1642
ISSN (online)	1545-4304
ISSN	0362-1642
DOI	10.1146/annurev.pharmtox.48.113006.094723
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Targeting the MDM2-p53 interaction for cancer therapy.

Shangary, Sanjeev / Wang, Shaomeng

Clinical cancer research : an official journal of the American Association for Cancer Research

2008 Volume 14, Issue 17, Page(s) 5318–5324

Abstract: p53 is a powerful tumor suppressor and is an attractive cancer therapeutic target because it can be functionally activated to eradicate tumors. The gene encoding p53 protein is mutated or deleted in half of human cancers, which inactivates its tumor ... ...

Abstract	p53 is a powerful tumor suppressor and is an attractive cancer therapeutic target because it can be functionally activated to eradicate tumors. The gene encoding p53 protein is mutated or deleted in half of human cancers, which inactivates its tumor suppressor activity. In the remaining cancers with wild-type p53 status, its function is effectively inhibited through direct interaction with the human murine double minute 2 (MDM2) oncoprotein. Blocking the MDM2-p53 interaction to reactivate the p53 function is a promising cancer therapeutic strategy. This review will highlight the advances in the design and development of small-molecule inhibitors of the MDM2-p53 interaction as a cancer therapeutic approach.
MeSH term(s)	Drug Delivery Systems ; Humans ; Models, Biological ; Neoplasms/drug therapy ; Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors ; Proto-Oncogene Proteins c-mdm2/metabolism ; Tumor Suppressor Protein p53/antagonists & inhibitors ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Tumor Suppressor Protein p53 ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2008-09-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-07-5136
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Article: Peptides derived from BH3 domains of Bcl-2 family members: a comparative analysis of inhibition of Bcl-2, Bcl-x(L) and Bax oligomerization, induction of cytochrome c release, and activation of cell death.

Shangary, Sanjeev / Johnson, Daniel E

Biochemistry

2002 Volume 41, Issue 30, Page(s) 9485–9495

Abstract: Overexpression of Bcl-2, an anti-apoptotic oncoprotein, is commonly observed in a variety of human malignancies and is associated with resistance to chemotherapy and radiotherapy. Although the precise mechanism of Bcl-2 action remains elusive, current ... ...

Abstract	Overexpression of Bcl-2, an anti-apoptotic oncoprotein, is commonly observed in a variety of human malignancies and is associated with resistance to chemotherapy and radiotherapy. Although the precise mechanism of Bcl-2 action remains elusive, current evidence indicates that Bcl-2 inhibits apoptosis by binding and inhibiting pro-apoptotic molecules such as Bax. Therefore, agents that disrupt the ability of Bcl-2, or other anti-apoptotic molecules, to bind to pro-apoptotic molecules may have therapeutic value. Several studies have shown that the BH3 domains of Bcl-2 and Bax are critically important for Bax/Bcl-2 heterodimerization. In this report, we designed and synthesized peptides based on the BH3 domains of three distinct Bcl-2 family members, Bcl-2, Bax and Bad. In vitro interaction assays were used to compare the abilities of the different peptides to inhibit Bax/Bcl-2 and Bax/Bcl-x(L) heterodimerization, as well as Bcl-2 and Bax homodimerization. Bax BH3 peptide (20-amino acids) potently inhibited both Bax/Bcl-2 and Bax/Bcl-x(L) interactions, exhibiting IC(50) values of 15 and 9.5 microM, respectively. The Bad BH3 peptide (21 amino acids) was slightly more potent than Bax BH3 at inhibiting Bax/Bcl-x(L) but failed to disrupt Bax/Bcl-2. Bcl-2 BH3 peptide (20-amino acids) was inactive toward Bax/Bcl-2 and had only a weak inhibitory effect on Bax/Bcl-x(L) heterodimerization. All three BH3 peptides failed to significantly inhibit homodimerization of Bcl-2 or Bax. Consistent with its ability to disrupt Bax/Bcl-2 heterodimerization, Bax BH3 peptide was able to overcome Bcl-2 overexpression and induce cytochrome c release from mitochondria of Bcl-2-overexpressing Jurkat T leukemic cells. Bad BH3 peptide, while potently inducing cytochrome c release in wild-type Jurkat cells, only partially overcame the effects of Bcl-2 overexpression. Bcl-2 BH3 failed to induce cytochrome c release, even in wild-type cells. Delivery of the Bax BH3 and Bad BH3 peptides into wild-type Jurkat cells induced comparable levels of cell death. In cells overexpressing Bcl-2, the potency of Bax BH3 peptide was similar to that seen in wild-type cells, while the efficacy of Bad BH3 peptide was reduced. By contrast, in Bcl-x(L)-overexpressing cells, Bad BH3 exhibited greater cell-killing activity than Bax BH3. The Bcl-2 BH3 peptide and a mutant Bax BH3 peptide had no appreciable effect on Jurkat cells. Together, our data suggest that agents based on the Bax BH3 domain may have therapeutic value in cancers overexpressing Bcl-2, while agents based on the BH3 domain of Bad may be more useful for tumors overexpressing Bcl-x(L).
MeSH term(s)	Amino Acid Sequence ; Cell Death ; Cytochrome c Group/metabolism ; Dimerization ; Enzyme Induction ; Humans ; Jurkat Cells ; Mitochondria/enzymology ; Molecular Sequence Data ; Proto-Oncogene Proteins/antagonists & inhibitors ; Proto-Oncogene Proteins/chemistry ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2/chemistry ; Proto-Oncogene Proteins c-bcl-2/metabolism ; bcl-2-Associated X Protein ; bcl-X Protein
Chemical Substances	BAX protein, human ; BCL2L1 protein, human ; Cytochrome c Group ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins c-bcl-2 ; bcl-2-Associated X Protein ; bcl-X Protein
Language	English
Publishing date	2002-07-16
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi025605h
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Article ; Online: Optimization and validation of mitochondria-based functional assay as a useful tool to identify BH3-like molecules selectively targeting anti-apoptotic Bcl-2 proteins.

Long, Jianting / Liu, Liu / Nikolovska-Coleska, Zaneta / Shangary, Sanjeev / Yi, Han / Wang, Shenming / Wang, Shaomeng

BMC biotechnology

2013 Volume 13, Page(s) 45

Abstract: Background: Mitochondrial outer membrane permeabilization (MOMP) is a crucial step leading to apoptotic destruction of cancer cells. Bcl-2 family proteins delicately regulate mitochondrial outer membrane integrity through protein-protein interactions, ... ...

Abstract	Background: Mitochondrial outer membrane permeabilization (MOMP) is a crucial step leading to apoptotic destruction of cancer cells. Bcl-2 family proteins delicately regulate mitochondrial outer membrane integrity through protein-protein interactions, which makes the mitochondrion an ideal cell-free system for screening molecules targeting the Bcl-2 anti-apoptotic proteins. But assay conditions need to be optimized for more reliable results. In this study, we aimed at establishing a reliable functional assay using mitochondria isolated from breast cancer cells to decipher the mode of action of BH3 peptides derived from BH3-only proteins. In this study, high ionic strength buffer was adopted during the initiation of MOMP. Mitochondria isolated from human breast cancer cell lines with distinct expression patterns of Bcl-2 anti-apoptotic proteins were permeabilized by different BH3 peptides alone or in combination, with or without the presence of recombinant anti-apoptotic Bcl-2 family proteins. Cytochrome C and Smac/Diablo were tested in both supernatants and mitochondrial pellets by Western blotting. Results: Sufficient ionic strength was required for optimal release of Cytochrome C. Bad and Noxa BH3 peptides exhibited their bona fide antagonistic effects against Bcl-2/Bcl-xL and Mcl-1 proteins, respectively, whereas Bim BH3 peptide antagonized all three anti-apoptotic Bcl-2 members. Bad and Noxa peptides synergized with each other in the induction of MOMP when mitochondria were dually protected by both Bcl-2/Bcl-xL and Mcl-1. Conclusions: This method based on MOMP is a useful screening tool for identifying BH3 mimetics with selective toxicity against breast cancer cell mitochondria protected by the three major Bcl-2 anti-apoptotic proteins.
MeSH term(s)	Apoptosis/genetics ; Apoptosis/physiology ; Apoptosis Regulatory Proteins ; BH3 Interacting Domain Death Agonist Protein/metabolism ; Blotting, Western ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell-Free System ; Cytochromes c/metabolism ; Female ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reproducibility of Results ; Surface Plasmon Resonance ; bcl-Associated Death Protein/metabolism ; bcl-X Protein/antagonists & inhibitors
Chemical Substances	Apoptosis Regulatory Proteins ; BAD protein, human ; BCL2L1 protein, human ; BH3 Interacting Domain Death Agonist Protein ; DIABLO protein, human ; Intracellular Signaling Peptides and Proteins ; MCL1 protein, human ; Mitochondrial Proteins ; Myeloid Cell Leukemia Sequence 1 Protein ; PMAIP1 protein, human ; Proto-Oncogene Proteins c-bcl-2 ; bcl-Associated Death Protein ; bcl-X Protein ; Cytochromes c (9007-43-6)
Language	English
Publishing date	2013-05-24
Publishing country	England
Document type	Journal Article
ISSN	1472-6750
ISSN (online)	1472-6750
DOI	10.1186/1472-6750-13-45
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Article ; Online: Targeting antiapoptotic Bcl-2 family members with cell-permeable BH3 peptides induces apoptosis signaling and death in head and neck squamous cell carcinoma cells.

Li, Rongxiu / Boehm, Amanda L / Miranda, Michelle B / Shangary, Sanjeev / Grandis, Jennifer R / Johnson, Daniel E

Neoplasia (New York, N.Y.)

2007 Volume 9, Issue 10, Page(s) 801–811

Abstract: Head and neck squamous cell carcinomas (HNSCC) are frequently characterized by chemotherapy and radiation resistance, and by overexpression of Bcl-XL, an antiapoptotic member of the Bcl-2 protein family. In this report we examined whether cell-permeable ... ...

Abstract	Head and neck squamous cell carcinomas (HNSCC) are frequently characterized by chemotherapy and radiation resistance, and by overexpression of Bcl-XL, an antiapoptotic member of the Bcl-2 protein family. In this report we examined whether cell-permeable peptides derived from the BH3 domains of proapoptotic Bax, Bad, or Bak could be used to target Bcl-XL and/or Bcl-2 in HNSCC cells, and induce apoptotic death in these cells. To render the peptides cell permeable, Antennapedia (Ant) or polyarginine (R8) peptide transduction domains were fused to the amino termini. Fluorescence microscopy of peptide-treated HNSCC cells revealed that the BH3 peptides colocalized with mitochondria, the site of Bcl-XL and Bcl-2 expression. By contrast, a mutant peptide (BaxE BH3) which cannot bind Bcl-XL or Bcl-2 was diffusely localized throughout the cytoplasm. Treatment of three HNSCC cell lines (1483, UM-22A, UM-22B) with the wild-type BH3 peptides resulted in loss of viability and induction of apoptosis, as assessed by MTS assays and annexin V staining. In general, Ant-conjugated peptides were more potent than R8-conjugated peptides, and Bad BH3 peptide was typically more potent than Bax BH3 or Bak BH3. Treatment of purified HNSCC mitochondria with BH3 peptides resulted in robust release of cytochrome c. Thus, the relative apoptosis resistance of HNSCC cells is not due to a deficit in this step of the intrinsic, mitochondrial-mediated apoptosis pathway. We conclude that cell-permeable BH3 peptides can be used to target Bcl-XL and/or Bcl-2 in HNSCC, and targeting of these proteins may have therapeutic value in the treatment of this disease.
MeSH term(s)	Amino Acid Sequence ; Antennapedia Homeodomain Protein/chemistry ; Antennapedia Homeodomain Protein/metabolism ; Apoptosis/physiology ; BH3 Interacting Domain Death Agonist Protein/chemistry ; BH3 Interacting Domain Death Agonist Protein/metabolism ; Carcinoma, Squamous Cell/metabolism ; Carcinoma, Squamous Cell/pathology ; Cell Line, Tumor ; Cell Membrane Permeability ; Flow Cytometry ; Head and Neck Neoplasms/metabolism ; Head and Neck Neoplasms/pathology ; Humans ; Immunoblotting ; Microscopy, Fluorescence ; Mitochondria/metabolism ; Molecular Sequence Data ; Peptides/chemistry ; Peptides/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism
Chemical Substances	Antennapedia Homeodomain Protein ; BH3 Interacting Domain Death Agonist Protein ; BID protein, human ; Peptides ; Proto-Oncogene Proteins c-bcl-2 ; polyarginine (25212-18-4)
Language	English
Publishing date	2007-10-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1483840-0
ISSN	1476-5586 ; 1522-8002
ISSN (online)	1476-5586
ISSN	1522-8002
DOI	10.1593/neo.07394
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Article: (-)-Gossypol acts directly on the mitochondria to overcome Bcl-2- and Bcl-X(L)-mediated apoptosis resistance.

Oliver, Christopher L / Miranda, Michelle B / Shangary, Sanjeev / Land, Stephanie / Wang, Shaomeng / Johnson, Daniel E

Molecular cancer therapeutics

2005 Volume 4, Issue 1, Page(s) 23–31

Abstract: Aberrant overexpression of antiapoptotic members of the Bcl-2 protein family, including Bcl-2 and Bcl-X(L), contributes to malignant transformation and subsequent resistance to traditional chemotherapeutics. Thus, these proteins represent attractive ... ...

Abstract	Aberrant overexpression of antiapoptotic members of the Bcl-2 protein family, including Bcl-2 and Bcl-X(L), contributes to malignant transformation and subsequent resistance to traditional chemotherapeutics. Thus, these proteins represent attractive targets for novel anticancer agents. The small molecule, gossypol, was initially investigated as a contraceptive agent, but subsequently has been shown to possess anticancer properties in vitro and in vivo. Recently gossypol has been found to bind to Bcl-X(L) and, with less affinity, to Bcl-2. Here we investigate the ability of the (-) enantiomer of gossypol, (-)-gossypol, to overcome the apoptosis resistance conferred by Bcl-2 or Bcl-X(L) overexpression in Jurkat T leukemia cells. (-)-Gossypol potently induced cell death in Jurkat cells overexpressing Bcl-2 (IC50, 18.1+/-2.6 micromol/L) or Bcl-X(L) (IC50, 22.9+/-3.7 micromol/L). Vector-transfected control cells were also potently killed by (-)-gossypol (IC50, 7.0+/-2.7 micromol/L). By contrast, the chemotherapy drug etoposide only induced efficient killing of vector-transfected cells (IC50, 9.6+/-2.3 micromol/L). Additionally, (-)-gossypol was more efficient than etoposide at inducing caspase-3 activation and phosphatidylserine externalization in the setting of Bcl-2 or Bcl-X(L) overexpression. (-)-Gossypol-induced apoptosis was associated with Bak activation and release of cytochrome c from mitochondria, suggesting a mitochondrial-mediated apoptotic mechanism. Moreover, (-)-gossypol treatment of isolated mitochondria purified from Bcl-2-overexpressing cells also resulted in cytochrome c release, indicating a possible direct action on Bcl-2 present in the mitochondrial outer membrane. Taken together, these results suggest that (-)-gossypol is a potent and novel therapeutic able to overcome apoptosis resistance by specifically targeting the activity of antiapoptotic Bcl-2 family members. (-)-Gossypol may be a promising new agent to treat malignancies that are resistant to conventional therapies.
MeSH term(s)	Apoptosis/drug effects ; Cell Survival/drug effects ; Etoposide/toxicity ; Gossypol/pharmacology ; Humans ; Jurkat Cells ; Mitochondria/drug effects ; Mitochondria/metabolism ; Proto-Oncogene Proteins c-bcl-2/drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Transfection ; bcl-X Protein
Chemical Substances	BCL2L1 protein, human ; Proto-Oncogene Proteins c-bcl-2 ; bcl-X Protein ; Etoposide (6PLQ3CP4P3) ; Gossypol (KAV15B369O)
Language	English
Publishing date	2005-01-18
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
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Article: Sequence and helicity requirements for the proapoptotic activity of Bax BH3 peptides.

Shangary, Sanjeev / Oliver, Christopher L / Tillman, Tommy S / Cascio, Michael / Johnson, Daniel E

Molecular cancer therapeutics

2004 Volume 3, Issue 11, Page(s) 1343–1354

Abstract: Overexpression of the antiapoptotic proteins Bcl-2 and Bcl-XL is commonly observed in human malignancies and contributes to chemotherapy and radiation resistance. Bcl-2 and Bcl-XL inhibit apoptosis by binding to proapoptotic proteins such as Bax, thereby ...

Abstract	Overexpression of the antiapoptotic proteins Bcl-2 and Bcl-XL is commonly observed in human malignancies and contributes to chemotherapy and radiation resistance. Bcl-2 and Bcl-XL inhibit apoptosis by binding to proapoptotic proteins such as Bax, thereby preventing chemotherapy-induced or radiation-induced release of cytochrome c from mitochondria and subsequent activation of the caspase protease cascade. Efforts to inhibit Bcl-2 or Bcl-XL function in tumor cells have focused on developing agents to inhibit the interactions of these proteins with proapoptotic proteins. Peptides derived from the BH3 domains of proapoptotic proteins have been shown to disrupt the interactions of Bcl-2 and Bcl-XL with key binding partners in cell-free reactions and to promote cellular apoptosis. However, less is known about the targets of BH3 peptides in intact cells as well as the sequence, length, and conformational requirements for peptide biological activity. In this report, we show that cell-permeable Bax BH3 peptides physically disrupt Bax/Bcl-2 heterodimerization in intact cells and that this disruption correlates with peptide-induced cell death. A point-mutant, control peptide that failed to disrupt intracellular Bax/Bcl-2 interactions also failed to promote apoptosis. To determine important sequence, length, and structural requirements for peptide activity, we generated and systematically analyzed the biological activities of 17 Bax BH3 peptide variants. Peptides were quantitatively examined for their ability to inhibit Bax/Bcl-2 and Bax/Bcl-XL heterodimerization in vitro and to promote cytochrome c release from mitochondria isolated from Jurkat, HL-60, U937, and PC-3 cells. Our results define 15 amino acids as the minimal length required for Bax BH3 peptide biological activity and show that amino acids COOH terminal to the BH3 core sequence are less critical than those located NH2 terminal to the core. In addition, circular dichroism spectroscopy revealed that high alpha-helical content generally correlated with, but was not sufficient for, peptide activity. Taken together, these studies provide a basis for future optimization of Bax BH3 peptide as a therapeutic anticancer agent.
MeSH term(s)	Amino Acid Sequence ; Apoptosis/drug effects ; Cell Line, Tumor ; Circular Dichroism ; Cytochromes c/metabolism ; Dimerization ; Humans ; Mitochondria/drug effects ; Mitochondria/metabolism ; Molecular Sequence Data ; Mutation/genetics ; Peptide Fragments/chemistry ; Peptide Fragments/genetics ; Peptide Fragments/pharmacology ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2/chemistry ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Proto-Oncogene Proteins c-bcl-2/pharmacology ; Sequence Alignment ; Signal Transduction/drug effects ; bcl-2-Associated X Protein
Chemical Substances	BAX protein, human ; Peptide Fragments ; Proto-Oncogene Proteins c-bcl-2 ; bcl-2-Associated X Protein ; Cytochromes c (9007-43-6)
Language	English
Publishing date	2004-11-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
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Article: Lyn regulates the cell death response to ultraviolet radiation through c-Jun N terminal kinase-dependent Fas ligand activation.

Shangary, Sanjeev / Lerner, Edwina C / Zhan, Qimin / Corey, Seth J / Smithgall, Thomas E / Baskaran, R

Experimental cell research

2003 Volume 289, Issue 1, Page(s) 67–76

Abstract: The Src-related tyrosine kinase, Lyn, plays an important role in mediating the cell cycle arrest and cell death response to genotoxic agents such as ionizing radiation. In this report we provide evidence to show that the catalytic function of Lyn is ... ...

Abstract	The Src-related tyrosine kinase, Lyn, plays an important role in mediating the cell cycle arrest and cell death response to genotoxic agents such as ionizing radiation. In this report we provide evidence to show that the catalytic function of Lyn is required for ultraviolet radiation (UV)- and methyl methanesulfonate (MMS)- but not for cisplatin (CDDP)- or ionizing radiation (IR)-induced cell death. Consequently, fibroblasts deficient in Lyn function were protected against cell death induction by UV and MMS, but showed normal cell death to IR and CDDP treatment. In Lyn(-/-) cells, UV-induced activation of stress-responsive kinases, Erk1/2 and p38, was normal; however, JNK activation was diminished. In addition, FasL induction by UV was also diminished in these cells. Reintroduction of wild-type Lyn restored JNK activation, FasL induction, and sensitivity to UV and MMS. A role for FasL in the cell death induction by Lyn-JNK signaling is indicated by the inhibition of cell death response by FasL neutralizing antibody. Together, the results support the presence of the Lyn-JNK signaling pathway that mediates the cell death response to UV and MMS treatment through FasL induction.
MeSH term(s)	Animals ; Antineoplastic Agents, Alkylating/pharmacology ; Cell Death/physiology ; Cell Death/radiation effects ; Cisplatin/pharmacology ; Down-Regulation/physiology ; Down-Regulation/radiation effects ; Eukaryotic Cells/enzymology ; Eukaryotic Cells/radiation effects ; Fas Ligand Protein ; Fetus ; HeLa Cells ; Humans ; JNK Mitogen-Activated Protein Kinases ; Membrane Glycoproteins/metabolism ; Membrane Glycoproteins/radiation effects ; Methyl Methanesulfonate/pharmacology ; Mice ; Mice, Knockout ; Mitogen-Activated Protein Kinases/metabolism ; Mitogen-Activated Protein Kinases/radiation effects ; Radiation, Ionizing ; Ultraviolet Rays/adverse effects ; src-Family Kinases/metabolism ; src-Family Kinases/radiation effects
Chemical Substances	Antineoplastic Agents, Alkylating ; FASLG protein, human ; Fas Ligand Protein ; Fasl protein, mouse ; Membrane Glycoproteins ; Methyl Methanesulfonate (AT5C31J09G) ; lyn protein-tyrosine kinase (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2003-09-10
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/s0014-4827(03)00234-9
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Article: Discovery of a nanomolar inhibitor of the human murine double minute 2 (MDM2)-p53 interaction through an integrated, virtual database screening strategy.

Lu, Yipin / Nikolovska-Coleska, Zaneta / Fang, Xueliang / Gao, Wei / Shangary, Sanjeev / Qiu, Su / Qin, Dongguang / Wang, Shaomeng

Journal of medicinal chemistry

2006 Volume 49, Issue 13, Page(s) 3759–3762

Abstract: An integrated, virtual database screening strategy has led to 7-[anilino(phenyl)methyl]-2-methyl-8-quinolinol (4, NSC 66811) as a novel inhibitor of the murine double minute 2 (MDM2)-p53 interaction. This quinolinol binds to MDM2 with a Ki of 120 nM and ... ...

Abstract	An integrated, virtual database screening strategy has led to 7-[anilino(phenyl)methyl]-2-methyl-8-quinolinol (4, NSC 66811) as a novel inhibitor of the murine double minute 2 (MDM2)-p53 interaction. This quinolinol binds to MDM2 with a Ki of 120 nM and activates p53 in cancer cells with a mechanism of action consistent with targeting the MDM2-p53 interaction. It mimics three p53 residues critical in the binding to MDM2 and represents a promising new class of non-peptide inhibitors of the MDM2-p53 interaction.
MeSH term(s)	Aniline Compounds/chemistry ; Aniline Compounds/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Binding Sites ; Binding, Competitive ; Cell Line, Tumor ; Crystallography, X-Ray ; Databases, Factual ; HCT116 Cells ; Humans ; Hydroxyquinolines/chemistry ; Hydroxyquinolines/pharmacology ; Models, Molecular ; Molecular Mimicry ; Mutation ; Proto-Oncogene Proteins c-mdm2/chemistry ; Proto-Oncogene Proteins c-mdm2/metabolism ; Stereoisomerism ; Tumor Suppressor Protein p53/chemistry ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	7-(anilino(phenyl)methyl)-2-methyl-8-quinolinol ; Aniline Compounds ; Antineoplastic Agents ; Hydroxyquinolines ; Tumor Suppressor Protein p53 ; Mdm2 protein, mouse (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2006-06-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm060023+
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Article: ATM is activated in response to N-methyl-N'-nitro-N-nitrosoguanidine-induced DNA alkylation.

Adamson, Aaron W / Kim, Wan-Ju / Shangary, Sanjeev / Baskaran, R / Brown, Kevin D

The Journal of biological chemistry

2002 Volume 277, Issue 41, Page(s) 38222–38229

Abstract: p53 plays an important role in response to ionizing radiation by regulating cell cycle progression and triggering apoptosis. These activities are controlled, in part, by the phosphorylation of p53 by the protein kinase ATM. Recent evidence indicates that ...

Abstract	p53 plays an important role in response to ionizing radiation by regulating cell cycle progression and triggering apoptosis. These activities are controlled, in part, by the phosphorylation of p53 by the protein kinase ATM. Recent evidence indicates that the monofunctional DNA alkylating agent N-methyl-N'-nitro-N- nitrosoguanidine (MNNG) also triggers up-regulation and phosphorylation of p53; however, the mechanism(s) responsible for this are unknown. We observed that in MNNG-treated normal human fibroblasts, up-regulation and phosphorylation of p53 was sensitive to the ATM kinase inhibitor wortmannin. ATM-deficient fibroblasts exhibited a delay in p53 up-regulation indicating a role for ATM in triggering the MNNG-induced response. Likewise, a mismatch repair (MMR)-deficient colorectal tumor line failed to show rapid up-regulation of p53. However, unlike ATM-deficient cells, these MMR-deficient cells displayed rapid phosphorylation of the p53 residue serine 15 after MNNG. In vitro kinase assays indicate that ATM is rapidly activated in both normal and MMR-deficient cells in response to MNNG. Using a number of morphological and biochemical approaches, we failed to observe MNNG-induced apoptosis in normal human fibroblasts, suggesting that apoptosis-induced DNA strand breaks are not required for the activation of ATM in response to MNNG. Comet assays indicated that strand breaks accumulated, and p53 up-regulation/phosphorylation occurred quite rapidly (within 30 min) after MNNG treatment, suggesting that DNA strand breaks that arise during the repair process activate ATM. These findings indicate that ATM activation is not limited to the ionizing radiation-induced response and potentially plays an important role in response to DNA alkylation.
MeSH term(s)	Alkylation ; Androstadienes/pharmacology ; Apoptosis/drug effects ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; Cells, Cultured ; DNA/chemistry ; DNA/metabolism ; DNA-Binding Proteins ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Fibroblasts/cytology ; Fibroblasts/drug effects ; Fibroblasts/physiology ; Fibroblasts/radiation effects ; Humans ; Methylnitronitrosoguanidine/pharmacology ; Protein-Serine-Threonine Kinases/metabolism ; Radiation, Ionizing ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins ; Up-Regulation ; Wortmannin
Chemical Substances	Androstadienes ; Cell Cycle Proteins ; DNA-Binding Proteins ; Enzyme Inhibitors ; Tumor Suppressor Protein p53 ; Tumor Suppressor Proteins ; Methylnitronitrosoguanidine (12H3O2UGSF) ; DNA (9007-49-2) ; ATM protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Wortmannin (XVA4O219QW)
Language	English
Publishing date	2002-07-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M204409200
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