Proteases to die for

Cryns, Vincent L.; Yuan, Junying

doi:10.1101/gad.12.11.1551

Cited by 1,172 publications

(911 citation statements)

References 237 publications

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“…They are known to play crucial roles in programmed cell death or apoptosis. 44,45 Among the caspases, the effector caspases (e.g., caspase-3 and caspase-7) can trigger the mitochondrial apoptosis cascade. It has been previously reported that 6-OHDA causes cell death via an intrinsic apoptotic pathway in MN9D cells.…”

Section: Acs Chemical Neurosciencementioning

confidence: 99%

D-512 and D-440 as Novel Multifunctional Dopamine Agonists: Characterization of Neuroprotection Properties and Evaluation of In Vivo Efficacy in a Parkinson’s Disease Animal Model

Santra

Shah

et al. 2013

ACS Chem. Neurosci.

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In this Article, we have demonstrated the in vivo efficacy of D-512 and D-440 in a 6-OHDA-induced unilaterally lesioned rat model experiment, a Parkinson's disease animal model. D-512 is a novel highly potent D2/D3 agonist, and D-440 is a novel highly selective D3 agonist. We evaluated the neuroprotective properties of D-512 and D-440 in the dopaminergic MN9D cells. Cotreatment of these two drugs with 6-OHDA and MPP+ significantly attenuated and reversed 6-OHDA-and MPP+-induced toxicity in a dosedependent manner in the dopaminergic MN9D cells. The inhibition of caspase 3/7 and lipid peroxidation activities along with the restoration of tyrosine hydroxylase levels by D-512 in 6-OHDA-treated cells may partially explain the mechanism of its neuroprotective property. Furthermore, studies were carried out to elucidate the time-dependent changes in the pERK1/2 and pAkt, two kinases implicated in cell survival and apoptosis, levels upon treatment with 6-OHDA in presence of D-512. The neuroprotective property exhibited by these drugs was independent of their dopamine-agonist activity, which is consistent with our multifunctional drug-development approach that is focused on the generation of disease-modifying symptomatic-treatment agents for Parkinson's disease.

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Section: Acs Chemical Neurosciencementioning

confidence: 99%

D-512 and D-440 as Novel Multifunctional Dopamine Agonists: Characterization of Neuroprotection Properties and Evaluation of In Vivo Efficacy in a Parkinson’s Disease Animal Model

Santra

Shah

et al. 2013

ACS Chem. Neurosci.

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“…As shown in Figure 3b, when compared to the maximal LDH release (MLR), early LDH release into the cytoplasm by 1 hr did not occur after exposure to 30 M p53p-Ant. The positive control for necrosis, 30 M p53(15)Ant that is a p53 N-terminal peptide (aa [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] shown by us to induce only necrosis without any evidence for apoptosis, 36,37 was carried out simultaneously. The N-terminal p53 peptide induced significant necrosis as evidenced by an early LDH release assay by 1 hr.…”

Section: P53 C-terminal Peptide-induced Cell Death: Apoptosis Vs Necmentioning

confidence: 99%

“…This activates poly (ADP-ribose) polymerase (PARP) and ICE family proteases, triggering a cascade of apoptotic processes. 19,20 Apoptosis involves a series of complex biochemical events and is regulated by several pathways, including members of the Bcl-2 family. Bcl-2 is a negative regulator of apoptosis and its' activity is modulated by homodimerization or heterodimerization association with promoters of apoptosis such as Bax and Bad.…”

mentioning

confidence: 99%

Selective induction of apoptosis through the FADD/caspase‐8 pathway by a p53 c‐terminal peptide in human pre‐malignant and malignant cells

Mao

Rosal

et al. 2005

Intl Journal of Cancer

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A p53 C-terminal peptide (aa 361-382, p53p), fused at its Cterminus to the minimal carrier peptide of antennapedia (17 aa, Ant; p53p-Ant), induced rapid apoptosis in human cancer cells, via activation of the Fas pathway. We examined p53p-Ant mechanism of action, toxicity in various human normal, non-malignant, pre-malignant and malignant cancer cells and investigated its biophysical characteristics. p53p-Ant selectively induced cell death in only pre-malignant or malignant cells in a p53-dependent manner and was not toxic to normal and non-malignant cells. p53p-Ant was more toxic to the mutant p53 than wild-type p53 phenotype in H1299 lung cancer cells stably expressing human temperature-sensitive p53 mutant 143Ala. Surface plasmon resonance (BIACORE) analysis demonstrated that this peptide had higher binding affinity to mutant p53 as compared to wild-type p53. p53p-Ant induced-cell death had the classical morphological characteristics of apoptosis and had no features of necrosis. The The p53 tumor suppressor gene is one of the most commonly mutated genes found in human malignancies. 1 More than 50% of human tumors, including breast cancers, are associated with missense mutations or deletions of p53 and most of the missense mutations map to the DNA-binding domain of the protein. 2,3 p53 protein functions in the transcription of growth inhibiting genes, apoptosis, cell cycle arrest and DNA repair. 4 -6 p53 is a sequencespecific transcription factor that transactivates a number of genes whose products are involved in cell growth regulation. These include p21 (a cyclin-dependent kinase inhibitor known to arrest the cell cycle mainly in G1/S phase), GADD45 for DNA repair and Bax and Fas/APO-1 for apoptosis. 7-11 p53 induced Fas-FADD binding and transiently sensitized cells to Fas-induced apoptosis. 12 Programmed cell death depends on conserved structural moieties that transmit and regulate the death signal. This is most evident in death receptors of the tumor necrosis factor receptor (TNF-R) super-family. The intracellular regions of the Fas/CD95 and TNFR1 death receptors have a moderately well conserved NH2-region of about 80 residues that is required for death signalling and has been called the 'death domain' (DD). 13,14 Fas/CD95 induces rapid apoptosis upon binding to Fas ligand through the autocrine/paracrine signalling pathway. 15 When activated, the intracellular death domain in Fas/CD95 binds to FADD/MORT-1 at its C-terminus, which then recruits caspase-8 to FADD. A member of the TNF ligand family identified more recently is TNF-related apoptosis-inducing ligand (TRAIL). TRAIL shows high homology to Fas Ligand and binds to the TRAIL receptor family. TRAILinduced caspase activation shares many of same caspases involved in Fas/CD95 and TNF-induced cell death mechanisms. 16 FADD/ MORT-1 is a cytosolic adaptor protein, which is critical for signalling from Fas/APO-1 and other TNF-R family members. 17 Two protein interaction domains have been identified in FADD/ MORT-1. The C-terminal 'death domain' is needed for ...

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“…1 These apoptotic features are the consequence of regulated proteolysis processes. 2,3 The apoptotic potential of a cell has a profound effect on whether that cell might respond to an environmental stress. In tumor cells, modulation of apoptosis plays a significant role in the progression to malignancy.…”

Section: Introductionmentioning

confidence: 99%

Viral oncoapoptosis of human tumor cells

Aubert

Blaho

2003

Gene Ther

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Many cancer cells refractory to radiation treatment and chemotherapy proliferate because of loss of intrinsic programmed cell death (apoptosis) regulation. Consequently, the resolution of these cancers are many times outside the management capabilities of conventional therapeutics. We now report that replication-defective D27 herpes simplex virus (rd D27) triggers apoptosis in three representative transformed human cell lines. Susceptibility to virus-induced cell death is dependent on the abundance and distribution of modified p53 protein in the tumor cells indicating specific targeting of the treatment. Primary human and mouse fibroblast cells that produce modified p53 are resistant to rd D27 killing but not to apoptosis induced by nonviral environmental factors. These results suggest that induction of apoptosis by nonreplicating virus is a feasible genetic therapy approach for killing human cancer cells. Our findings may have important implications in designing novel virus-based anticancer strategies in appropriate animal model systems.

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Proteases to die for

Cited by 1,172 publications

References 237 publications

D-512 and D-440 as Novel Multifunctional Dopamine Agonists: Characterization of Neuroprotection Properties and Evaluation of In Vivo Efficacy in a Parkinson’s Disease Animal Model

D-512 and D-440 as Novel Multifunctional Dopamine Agonists: Characterization of Neuroprotection Properties and Evaluation of In Vivo Efficacy in a Parkinson’s Disease Animal Model

Selective induction of apoptosis through the FADD/caspase‐8 pathway by a p53 c‐terminal peptide in human pre‐malignant and malignant cells

Viral oncoapoptosis of human tumor cells

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