Showing papers by "David Baltimore published in 1998"
TL;DR: Daxx and FADD define two distinct apoptotic pathways downstream of Fas, which are sensitive to both Bcl-2 and dominant-negative JNK pathway components and acts cooperatively with the FADD pathway.
1,122 citations
TL;DR: It is found that CTLs inefficiently lysed primary cells infected with HIV-1 if the viral nef gene product was expressed and Nef protected infected cells by reducing the epitope density on their surface.
Abstract: Cytotoxic T lymphocytes (CTLs) lyse virally infected cells that display viral peptide epitopes in association with major histocompatibility complex (MHC) class I molecules on the cell surface. However, despite a strong CTL response directed against viral epitopes, untreated people infected with the human immunodeficiency virus (HIV-1) develop AIDS. To resolve this enigma, we have examined the ability of CTLs to recognize and kill infected primary T lymphocytes. We found that CTLs inefficiently lysed primary cells infected with HIV-1 if the viral nef gene product was expressed. Resistance of infected cells to CTL killing correlated with nef-mediated downregulation of MHC class I (ref. 1) and could be overcome by adding an excess of the relevant HIV-1 epitope as soluble peptide. Thus, Nef protected infected cells by reducing the epitope density on their surface. This effect of nef may allow evasion of CTL lysis by HIV-1-infected cells.
1,029 citations
TL;DR: Results demonstrate that murine CML recapitulates important features of human CML and should be an excellent model for addressing specific issues relating to the pathogenesis and treatment of this disease.
781 citations
TL;DR: The Fas death receptor can activate the Jun NH2-terminal kinase (JNK) pathway through the receptor-associated protein Daxx, which completes a signaling pathway from a cell surface death receptor to kinase cascades that modulate nuclear transcription factors.
Abstract: The Fas death receptor can activate the Jun NH2-terminal kinase (JNK) pathway through the receptor-associated protein Daxx. Daxx was found to activate the JNK kinase kinase ASK1, and overexpression of a kinase-deficient ASK1 mutant inhibited Fas- and Daxx-induced apoptosis and JNK activation. Fas activation induced Daxx to interact with ASK1, which consequently relieved an inhibitory intramolecular interaction between the amino- and carboxyl-termini of ASK1, activating its kinase activity. The Daxx-ASK1 connection completes a signaling pathway from a cell surface death receptor to kinase cascades that modulate nuclear transcription factors.
607 citations
TL;DR: It is shown that oligomerization of pro-caspases is sufficient to induce proteolytic generation of mature caspase subunits and activation of their cell death activity.
427 citations
TL;DR: It is found that Abl and Arg colocalize with each other and with actin microfilaments at the apical surface of the developing neuroepithelium, and can regulate the structure of the actin cytoskeleton.
408 citations
TL;DR: Control of the activation of apoptosis is important both in development and in protection against cancer and Facilitating the proximity of CED-3 zymogen molecules was found to induce caspase activation and cell death.
Abstract: Control of the activation of apoptosis is important both in development and in protection against cancer. In the classic genetic model Caenorhabditis elegans, the pro-apoptotic protein CED-4 activates the CED-3 caspase and is inhibited by the Bcl-2–like protein CED-9. Both processes are mediated by protein-protein interaction. Facilitating the proximity of CED-3 zymogen molecules was found to induce caspase activation and cell death. CED-4 protein oligomerized in cells and in vitro. This oligomerization induced CED-3 proximity and competed with CED-4:CED-9 interaction. Mutations that abolished CED-4 oligomerization inactivated its ability to activate CED-3. Thus, the mechanism of control is that CED-3 in CED-3:CED-4 complexes is activated by CED-4 oligomerization, which is inhibited by binding of CED-9 to CED-4.
293 citations
TL;DR: The results suggest that HIV-1 induces direct apoptosis of infected cells and kills T cells by a Fas-independent mechanism, and depletes CD4+ T cells in PBMCs from patients who have a genetically defective Fas pathway.
Abstract: The mechanism by which HIV-1 induces CD4+ T cell death is not known. A fundamental issue is whether HIV-1 primarily induces direct killing of infected cells or indirectly causes death of uninfected bystander cells. This question was studied using a reporter virus system in which infected cells are marked with the cell surface protein placental alkaline phosphatase (PLAP). Infection by HIV-PLAP of peripheral blood mononuclear cells (PBMCs) and T cell lines leads to rapid depletion of CD4+ T cells and induction of apoptosis. The great majority of HIV-induced T cell death in vitro involves direct loss of infected cells rather than indirect effects on uninfected bystander cells. Because of its proposed role in HIV-induced cell death, we also examined the Fas (CD95/Apo1) pathway in killing of T cells by HIV-1. Infected PBMCs or CEM cells display no increase in surface Fas relative to uninfected cells. In addition, HIV-1 kills CEM and Jurkat T cells in the presence of a caspase inhibitor that completely blocks Fas-mediated apoptosis. HIV-1 also depletes CD4+ T cells in PBMCs from patients who have a genetically defective Fas pathway. These results suggest that HIV-1 induces direct apoptosis of infected cells and kills T cells by a Fas-independent mechanism.
194 citations
TL;DR: Disruption of the mouse Atm gene, whose human counterpart is consistently mutated in ataxia-telangiectasia (A-T) patients, creates an A-T mouse model exhibiting most of the A- T-related systematic and cellular defects.
Abstract: Disruption of the mouse Atm gene, whose human counterpart is consistently mutated in ataxia-telangiectasia (A-T) patients, creates an A-T mouse model exhibiting most of the A-T-related systematic and cellular defects. While ATM plays a major role in signaling the p53 response to DNA strand break damage, Atm-/- p53-/- mice develop lymphomas earlier than Atm-/- or p53-/- mice, indicating that mutations in these two genes lead to synergy in tumorigenesis. The cell cycle G1/S checkpoint is abolished in Atm-/- p53-/- mouse embryonic fibroblasts (MEFs) following gamma -irradiation, suggesting that the partial G1 cell cycle arrest in Atm-/- cells following gamma -irradiation is due to the residual p53 response in these cells. In addition, the Atm-/- p21-/- MEFs are more severely defective in their cell cycle G1 arrest following gamma -irradiation than Atm-/- and p21-/- MEFs. The Atm-/- MEFs exhibit multiple cellular proliferative defects in culture, and an increased constitutive level of p21 in these cells might account for these cellular proliferation defects. Consistent with this notion, Atm-/- p21-/- MEFs proliferate similarly to wild-type MEFs and exhibit no premature senescence. These cellular proliferative defects are also rescued in Atm-/- p53-/- MEFs and little p21 can be detected in these cells, indicating that the abnormal p21 protein level in Atm-/- cells is also p53 dependent and leads to the cellular proliferative defects in these cells. However, the p21 mRNA level in Atm-/- MEFs is lower than that in Atm+/+ MEFs, suggesting that the higher level of constitutive p21 protein in Atm-/- MEFs is likely due to increased stability of the p21 protein.
105 citations
TL;DR: Current research efforts toward developing anti-HIV vaccines are reviewed and it is stressed that important steps have been taken and that as such there is room for optimism.
Abstract: Carole Heilman (Division of AIDS at the National Institutes of Allergy and Infectious Diseases) and David Baltimore (President of the California Institute of Technology) review current research efforts toward developing anti-HIV vaccines. While recognizing the extraordinary challenges involved in developing a vaccine, Heilman and Baltimore stress that important steps have been taken and that as such there is room for optimism.
59 citations
TL;DR: Unlike vaccines for many viruses, those for HIV may have to go beyond generating antibodies to fully activate the immune system, according to a report in The Lancet Oncology.
Abstract: Unlike vaccines for many viruses, those for HIV may have to go beyond generating antibodies. Devising approaches that will fully activate the immune system is far from simple
Patent•
12 Feb 1998
TL;DR: In this paper, the authors propose a method for the use of acides nucleiques codant for the proteine Daxx, which concerne egalement des polypeptides and fragments of ces derniers, ainsi que des anticorps correspondants.
Abstract: L'invention concerne des acides nucleiques codant pour la proteine Daxx, y compris des fragments et des variants fonctionnels biologiques de ceux-ci. L'invention concerne egalement des polypeptides et des fragments de ces derniers, qui sont codes par de tels acides nucleiques, ainsi que des anticorps correspondants. L'invention concerne egalement des procedes et des produits servant a l'utilisation de tels acides nucleiques et polypeptides.