Jesus Salvador - Academia.edu (original) (raw)

Papers by Jesus Salvador

Research paper thumbnail of Concurso Traslados Cuerpos de EEMM - ADJUDICACIÓN PROVISIONAL Provincia de Palencia.- Curso 2008-2009

Research paper thumbnail of Characterization of the Intracellular and the Plasma Membrane Ca 2+-ATPases in Fractionated Pig Brain Membranes Using Calcium Pump Inhibitors

Archives of Biochemistry and Biophysics, 1998

The intracellular free Ca 2/ concentration acts as a pluripotent signal for many neuronal functio... more The intracellular free Ca 2/ concentration acts as a pluripotent signal for many neuronal functions (1, 2).

Research paper thumbnail of SENSACIÓN DE FATIGA EN PACIENTES CON APNEAS DE SUEÑO Y MOVIMIENTOS PERIÓDICOS DE LAS PIERNAS

Research paper thumbnail of Gadd45a acts as a modifier locus for lymphoblastic lymphoma

Research paper thumbnail of Dimethylbenzanthracene Carcinogenesis in Gadd45a-null Mice Is Associated with Decreased DNA Repair and Increased Mutation Frequency

Mice lacking the Gadd45a gene are susceptible to ionizing radiationinduced tumors. Increased leve... more Mice lacking the Gadd45a gene are susceptible to ionizing radiationinduced tumors. Increased levels of Gadd45a transcript and protein are seen after treatment of cells with ionizing radiation as well as many other agents and treatments that damage DNA. Because cells deficient in Gadd45a were shown to have a partial defect in the global genomic repair component of the nucleotide excision repair pathway of UV-induced photoproducts, dimethylbenzanthracene (DMBA) carcinogenesis was investigated because this agent produces bulky adducts in DNA that are also repaired by nucleotide excision repair. Wild-type mice and mice deficient for Gadd45a were injected with a single i.p. dose of DMBA at 10 -14 days of age. The latency for spontaneous deaths was slightly decreased for Gadd45a-null mice compared with wild-type mice. At 17 months, all surviving animals were killed, and similar percentages of each genotype were found to have tumors. However, nearly twice as many Gadd45a-null than wild-type mice had multiple tumors, and three times as many had multiple malignant tumors. The predominant tumor types in wild-type mice were lymphoma and tumors of the intestines and liver. In Gadd45anull mice, there was a dramatic increase in female ovarian tumors, male hepatocellular tumors, and in vascular tumors in both sexes. In wild-type mice, this dose of DMBA induced a >5-fold increase in Gadd45a transcript in the spleen and ovary, whereas the increase in liver was >20-fold. Nucleotide excision repair, which repairs both UV-and DMBA-induced DNA lesions, was substantially reduced in Gadd45a-null lymphoblasts. Mutation frequency after DMBA treatment was threefold higher in Gadd45a-null liver compared with wild-type liver. Therefore, lack of basal and DMBA-induced Gadd45a may result in enhanced tumorigenesis because of decreased DNA repair and increased mutation frequency. Genomic instability, decreased cell cycle checkpoints, and partial loss of normal growth control in cells from Gadd45a-null mice may also contribute to this process.

Research paper thumbnail of Mice Lacking the p53Effector Gene Gadd45a Develop a Lupus-Like Syndrome

Immunity, 2002

Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stabil... more Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability and cell growth control. We have reported that one of the

Research paper thumbnail of The autoimmune suppressor Gadd45α inhibits the T cell alternative p38 activation pathway

Nature Immunology, 2005

The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have ... more The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have an alternative pathway in which T cell receptor-activated tyrosine kinase Zap70 phosphorylates p38 on Tyr323. Mice lacking Gadd45a, a small p38-binding molecule, develop a lupus-like autoimmune disease. Here we show that resting T cells but not B cells from Gadd45a À/À mice had spontaneously increased p38 activity in the absence of 'upstream' MAPK kinase activation. The p38 from resting Gadd45a À/À T cells was spontaneously phosphorylated on Tyr323, and its activity was specifically inhibited by recombinant Gadd45a in vitro. Thus, constitutive activation of T cell p38 through the alternative pathway is prevented by Gadd45a, the absence of which results in p38 activation, T cell hyperproliferation and autoimmunity.

Research paper thumbnail of Alternative p38 activation pathway mediated by T cell receptor–proximal tyrosine kinases

Nature Immunology, 2005

Signaling-responsive MAP kinases (MAPKs) are key in mediating immune responses and are activated ... more Signaling-responsive MAP kinases (MAPKs) are key in mediating immune responses and are activated through the phosphorylation of a Thr-X-Tyr motif by upstream MAPK kinases. Here we show that T cells stimulated through the T cell receptor (TCR) used an alternative mechanism in which p38 was phosphorylated on Tyr323 and subsequently autophosphorylated residues Thr180 and Tyr182. This required the TCR-proximal tyrosine kinase Zap70 but not the adaptor protein LAT, which was required for activation of extracellular signal-regulated protein kinase MAPKs. TCR activation of p38 lacking Tyr323 was diminished, and blocking of p38 activity prevented p38 dual phosphorylation in normal T cells but not in B cells. Thus, phosphorylation of Tyr323 dependent on the tyrosine kinase Lck and mediated by Zap70 serves as an important mechanism for TCR activation of p38 in T cells.

Research paper thumbnail of Gadd45a acts as a modifier locus for lymphoblastic lymphoma

Research paper thumbnail of Dimethylbenzanthracene Carcinogenesis in Gadd45a-null Mice Is Associated with Decreased DNA Repair and Increased Mutation Frequency

Mice lacking the Gadd45a gene are susceptible to ionizing radiationinduced tumors. Increased leve... more Mice lacking the Gadd45a gene are susceptible to ionizing radiationinduced tumors. Increased levels of Gadd45a transcript and protein are seen after treatment of cells with ionizing radiation as well as many other agents and treatments that damage DNA. Because cells deficient in Gadd45a were shown to have a partial defect in the global genomic repair component of the nucleotide excision repair pathway of UV-induced photoproducts, dimethylbenzanthracene (DMBA) carcinogenesis was investigated because this agent produces bulky adducts in DNA that are also repaired by nucleotide excision repair. Wild-type mice and mice deficient for Gadd45a were injected with a single i.p. dose of DMBA at 10 -14 days of age. The latency for spontaneous deaths was slightly decreased for Gadd45a-null mice compared with wild-type mice. At 17 months, all surviving animals were killed, and similar percentages of each genotype were found to have tumors. However, nearly twice as many Gadd45a-null than wild-type mice had multiple tumors, and three times as many had multiple malignant tumors. The predominant tumor types in wild-type mice were lymphoma and tumors of the intestines and liver. In Gadd45anull mice, there was a dramatic increase in female ovarian tumors, male hepatocellular tumors, and in vascular tumors in both sexes. In wild-type mice, this dose of DMBA induced a >5-fold increase in Gadd45a transcript in the spleen and ovary, whereas the increase in liver was >20-fold. Nucleotide excision repair, which repairs both UV-and DMBA-induced DNA lesions, was substantially reduced in Gadd45a-null lymphoblasts. Mutation frequency after DMBA treatment was threefold higher in Gadd45a-null liver compared with wild-type liver. Therefore, lack of basal and DMBA-induced Gadd45a may result in enhanced tumorigenesis because of decreased DNA repair and increased mutation frequency. Genomic instability, decreased cell cycle checkpoints, and partial loss of normal growth control in cells from Gadd45a-null mice may also contribute to this process.

Research paper thumbnail of Mice Lacking the p53Effector Gene Gadd45a Develop a Lupus-Like Syndrome

Immunity, 2002

Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stabil... more Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability and cell growth control. We have reported that one of the

Research paper thumbnail of The autoimmune suppressor Gadd45α inhibits the T cell alternative p38 activation pathway

Nature Immunology, 2005

The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have ... more The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have an alternative pathway in which T cell receptor-activated tyrosine kinase Zap70 phosphorylates p38 on Tyr323. Mice lacking Gadd45a, a small p38-binding molecule, develop a lupus-like autoimmune disease. Here we show that resting T cells but not B cells from Gadd45a À/À mice had spontaneously increased p38 activity in the absence of 'upstream' MAPK kinase activation. The p38 from resting Gadd45a À/À T cells was spontaneously phosphorylated on Tyr323, and its activity was specifically inhibited by recombinant Gadd45a in vitro. Thus, constitutive activation of T cell p38 through the alternative pathway is prevented by Gadd45a, the absence of which results in p38 activation, T cell hyperproliferation and autoimmunity.

Research paper thumbnail of Alternative p38 activation pathway mediated by T cell receptor–proximal tyrosine kinases

Nature Immunology, 2005

Signaling-responsive MAP kinases (MAPKs) are key in mediating immune responses and are activated ... more Signaling-responsive MAP kinases (MAPKs) are key in mediating immune responses and are activated through the phosphorylation of a Thr-X-Tyr motif by upstream MAPK kinases. Here we show that T cells stimulated through the T cell receptor (TCR) used an alternative mechanism in which p38 was phosphorylated on Tyr323 and subsequently autophosphorylated residues Thr180 and Tyr182. This required the TCR-proximal tyrosine kinase Zap70 but not the adaptor protein LAT, which was required for activation of extracellular signal-regulated protein kinase MAPKs. TCR activation of p38 lacking Tyr323 was diminished, and blocking of p38 activity prevented p38 dual phosphorylation in normal T cells but not in B cells. Thus, phosphorylation of Tyr323 dependent on the tyrosine kinase Lck and mediated by Zap70 serves as an important mechanism for TCR activation of p38 in T cells.

Research paper thumbnail of Gadd45a acts as a modifier locus for lymphoblastic lymphoma

Research paper thumbnail of Dimethylbenzanthracene Carcinogenesis in Gadd45a-null Mice Is Associated with Decreased DNA Repair and Increased Mutation Frequency

Mice lacking the Gadd45a gene are susceptible to ionizing radiationinduced tumors. Increased leve... more Mice lacking the Gadd45a gene are susceptible to ionizing radiationinduced tumors. Increased levels of Gadd45a transcript and protein are seen after treatment of cells with ionizing radiation as well as many other agents and treatments that damage DNA. Because cells deficient in Gadd45a were shown to have a partial defect in the global genomic repair component of the nucleotide excision repair pathway of UV-induced photoproducts, dimethylbenzanthracene (DMBA) carcinogenesis was investigated because this agent produces bulky adducts in DNA that are also repaired by nucleotide excision repair. Wild-type mice and mice deficient for Gadd45a were injected with a single i.p. dose of DMBA at 10 -14 days of age. The latency for spontaneous deaths was slightly decreased for Gadd45a-null mice compared with wild-type mice. At 17 months, all surviving animals were killed, and similar percentages of each genotype were found to have tumors. However, nearly twice as many Gadd45a-null than wild-type mice had multiple tumors, and three times as many had multiple malignant tumors. The predominant tumor types in wild-type mice were lymphoma and tumors of the intestines and liver. In Gadd45anull mice, there was a dramatic increase in female ovarian tumors, male hepatocellular tumors, and in vascular tumors in both sexes. In wild-type mice, this dose of DMBA induced a >5-fold increase in Gadd45a transcript in the spleen and ovary, whereas the increase in liver was >20-fold. Nucleotide excision repair, which repairs both UV-and DMBA-induced DNA lesions, was substantially reduced in Gadd45a-null lymphoblasts. Mutation frequency after DMBA treatment was threefold higher in Gadd45a-null liver compared with wild-type liver. Therefore, lack of basal and DMBA-induced Gadd45a may result in enhanced tumorigenesis because of decreased DNA repair and increased mutation frequency. Genomic instability, decreased cell cycle checkpoints, and partial loss of normal growth control in cells from Gadd45a-null mice may also contribute to this process.

Research paper thumbnail of Mice Lacking the p53Effector Gene Gadd45a Develop a Lupus-Like Syndrome

Immunity, 2002

Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stabil... more Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability and cell growth control. We have reported that one of the

Research paper thumbnail of The autoimmune suppressor Gadd45α inhibits the T cell alternative p38 activation pathway

Nature Immunology, 2005

The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have ... more The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have an alternative pathway in which T cell receptor-activated tyrosine kinase Zap70 phosphorylates p38 on Tyr323. Mice lacking Gadd45a, a small p38-binding molecule, develop a lupus-like autoimmune disease. Here we show that resting T cells but not B cells from Gadd45a À/À mice had spontaneously increased p38 activity in the absence of 'upstream' MAPK kinase activation. The p38 from resting Gadd45a À/À T cells was spontaneously phosphorylated on Tyr323, and its activity was specifically inhibited by recombinant Gadd45a in vitro. Thus, constitutive activation of T cell p38 through the alternative pathway is prevented by Gadd45a, the absence of which results in p38 activation, T cell hyperproliferation and autoimmunity.

Research paper thumbnail of Alternative p38 activation pathway mediated by T cell receptor–proximal tyrosine kinases

Nature Immunology, 2005

Signaling-responsive MAP kinases (MAPKs) are key in mediating immune responses and are activated ... more Signaling-responsive MAP kinases (MAPKs) are key in mediating immune responses and are activated through the phosphorylation of a Thr-X-Tyr motif by upstream MAPK kinases. Here we show that T cells stimulated through the T cell receptor (TCR) used an alternative mechanism in which p38 was phosphorylated on Tyr323 and subsequently autophosphorylated residues Thr180 and Tyr182. This required the TCR-proximal tyrosine kinase Zap70 but not the adaptor protein LAT, which was required for activation of extracellular signal-regulated protein kinase MAPKs. TCR activation of p38 lacking Tyr323 was diminished, and blocking of p38 activity prevented p38 dual phosphorylation in normal T cells but not in B cells. Thus, phosphorylation of Tyr323 dependent on the tyrosine kinase Lck and mediated by Zap70 serves as an important mechanism for TCR activation of p38 in T cells.

Research paper thumbnail of JESUS

Research paper thumbnail of Concurso Traslados Cuerpos de EEMM - ADJUDICACIÓN PROVISIONAL Provincia de Palencia.- Curso 2008-2009

Research paper thumbnail of Characterization of the Intracellular and the Plasma Membrane Ca 2+-ATPases in Fractionated Pig Brain Membranes Using Calcium Pump Inhibitors

Archives of Biochemistry and Biophysics, 1998

The intracellular free Ca 2/ concentration acts as a pluripotent signal for many neuronal functio... more The intracellular free Ca 2/ concentration acts as a pluripotent signal for many neuronal functions (1, 2).

Research paper thumbnail of SENSACIÓN DE FATIGA EN PACIENTES CON APNEAS DE SUEÑO Y MOVIMIENTOS PERIÓDICOS DE LAS PIERNAS

Research paper thumbnail of Gadd45a acts as a modifier locus for lymphoblastic lymphoma

Research paper thumbnail of Dimethylbenzanthracene Carcinogenesis in Gadd45a-null Mice Is Associated with Decreased DNA Repair and Increased Mutation Frequency

Mice lacking the Gadd45a gene are susceptible to ionizing radiationinduced tumors. Increased leve... more Mice lacking the Gadd45a gene are susceptible to ionizing radiationinduced tumors. Increased levels of Gadd45a transcript and protein are seen after treatment of cells with ionizing radiation as well as many other agents and treatments that damage DNA. Because cells deficient in Gadd45a were shown to have a partial defect in the global genomic repair component of the nucleotide excision repair pathway of UV-induced photoproducts, dimethylbenzanthracene (DMBA) carcinogenesis was investigated because this agent produces bulky adducts in DNA that are also repaired by nucleotide excision repair. Wild-type mice and mice deficient for Gadd45a were injected with a single i.p. dose of DMBA at 10 -14 days of age. The latency for spontaneous deaths was slightly decreased for Gadd45a-null mice compared with wild-type mice. At 17 months, all surviving animals were killed, and similar percentages of each genotype were found to have tumors. However, nearly twice as many Gadd45a-null than wild-type mice had multiple tumors, and three times as many had multiple malignant tumors. The predominant tumor types in wild-type mice were lymphoma and tumors of the intestines and liver. In Gadd45anull mice, there was a dramatic increase in female ovarian tumors, male hepatocellular tumors, and in vascular tumors in both sexes. In wild-type mice, this dose of DMBA induced a >5-fold increase in Gadd45a transcript in the spleen and ovary, whereas the increase in liver was >20-fold. Nucleotide excision repair, which repairs both UV-and DMBA-induced DNA lesions, was substantially reduced in Gadd45a-null lymphoblasts. Mutation frequency after DMBA treatment was threefold higher in Gadd45a-null liver compared with wild-type liver. Therefore, lack of basal and DMBA-induced Gadd45a may result in enhanced tumorigenesis because of decreased DNA repair and increased mutation frequency. Genomic instability, decreased cell cycle checkpoints, and partial loss of normal growth control in cells from Gadd45a-null mice may also contribute to this process.

Research paper thumbnail of Mice Lacking the p53Effector Gene Gadd45a Develop a Lupus-Like Syndrome

Immunity, 2002

Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stabil... more Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability and cell growth control. We have reported that one of the

Research paper thumbnail of The autoimmune suppressor Gadd45α inhibits the T cell alternative p38 activation pathway

Nature Immunology, 2005

The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have ... more The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have an alternative pathway in which T cell receptor-activated tyrosine kinase Zap70 phosphorylates p38 on Tyr323. Mice lacking Gadd45a, a small p38-binding molecule, develop a lupus-like autoimmune disease. Here we show that resting T cells but not B cells from Gadd45a À/À mice had spontaneously increased p38 activity in the absence of 'upstream' MAPK kinase activation. The p38 from resting Gadd45a À/À T cells was spontaneously phosphorylated on Tyr323, and its activity was specifically inhibited by recombinant Gadd45a in vitro. Thus, constitutive activation of T cell p38 through the alternative pathway is prevented by Gadd45a, the absence of which results in p38 activation, T cell hyperproliferation and autoimmunity.

Research paper thumbnail of Alternative p38 activation pathway mediated by T cell receptor–proximal tyrosine kinases

Nature Immunology, 2005

Signaling-responsive MAP kinases (MAPKs) are key in mediating immune responses and are activated ... more Signaling-responsive MAP kinases (MAPKs) are key in mediating immune responses and are activated through the phosphorylation of a Thr-X-Tyr motif by upstream MAPK kinases. Here we show that T cells stimulated through the T cell receptor (TCR) used an alternative mechanism in which p38 was phosphorylated on Tyr323 and subsequently autophosphorylated residues Thr180 and Tyr182. This required the TCR-proximal tyrosine kinase Zap70 but not the adaptor protein LAT, which was required for activation of extracellular signal-regulated protein kinase MAPKs. TCR activation of p38 lacking Tyr323 was diminished, and blocking of p38 activity prevented p38 dual phosphorylation in normal T cells but not in B cells. Thus, phosphorylation of Tyr323 dependent on the tyrosine kinase Lck and mediated by Zap70 serves as an important mechanism for TCR activation of p38 in T cells.

Research paper thumbnail of Gadd45a acts as a modifier locus for lymphoblastic lymphoma

Research paper thumbnail of Dimethylbenzanthracene Carcinogenesis in Gadd45a-null Mice Is Associated with Decreased DNA Repair and Increased Mutation Frequency

Mice lacking the Gadd45a gene are susceptible to ionizing radiationinduced tumors. Increased leve... more Mice lacking the Gadd45a gene are susceptible to ionizing radiationinduced tumors. Increased levels of Gadd45a transcript and protein are seen after treatment of cells with ionizing radiation as well as many other agents and treatments that damage DNA. Because cells deficient in Gadd45a were shown to have a partial defect in the global genomic repair component of the nucleotide excision repair pathway of UV-induced photoproducts, dimethylbenzanthracene (DMBA) carcinogenesis was investigated because this agent produces bulky adducts in DNA that are also repaired by nucleotide excision repair. Wild-type mice and mice deficient for Gadd45a were injected with a single i.p. dose of DMBA at 10 -14 days of age. The latency for spontaneous deaths was slightly decreased for Gadd45a-null mice compared with wild-type mice. At 17 months, all surviving animals were killed, and similar percentages of each genotype were found to have tumors. However, nearly twice as many Gadd45a-null than wild-type mice had multiple tumors, and three times as many had multiple malignant tumors. The predominant tumor types in wild-type mice were lymphoma and tumors of the intestines and liver. In Gadd45anull mice, there was a dramatic increase in female ovarian tumors, male hepatocellular tumors, and in vascular tumors in both sexes. In wild-type mice, this dose of DMBA induced a >5-fold increase in Gadd45a transcript in the spleen and ovary, whereas the increase in liver was >20-fold. Nucleotide excision repair, which repairs both UV-and DMBA-induced DNA lesions, was substantially reduced in Gadd45a-null lymphoblasts. Mutation frequency after DMBA treatment was threefold higher in Gadd45a-null liver compared with wild-type liver. Therefore, lack of basal and DMBA-induced Gadd45a may result in enhanced tumorigenesis because of decreased DNA repair and increased mutation frequency. Genomic instability, decreased cell cycle checkpoints, and partial loss of normal growth control in cells from Gadd45a-null mice may also contribute to this process.

Research paper thumbnail of Mice Lacking the p53Effector Gene Gadd45a Develop a Lupus-Like Syndrome

Immunity, 2002

Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stabil... more Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability and cell growth control. We have reported that one of the

Research paper thumbnail of The autoimmune suppressor Gadd45α inhibits the T cell alternative p38 activation pathway

Nature Immunology, 2005

The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have ... more The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have an alternative pathway in which T cell receptor-activated tyrosine kinase Zap70 phosphorylates p38 on Tyr323. Mice lacking Gadd45a, a small p38-binding molecule, develop a lupus-like autoimmune disease. Here we show that resting T cells but not B cells from Gadd45a À/À mice had spontaneously increased p38 activity in the absence of 'upstream' MAPK kinase activation. The p38 from resting Gadd45a À/À T cells was spontaneously phosphorylated on Tyr323, and its activity was specifically inhibited by recombinant Gadd45a in vitro. Thus, constitutive activation of T cell p38 through the alternative pathway is prevented by Gadd45a, the absence of which results in p38 activation, T cell hyperproliferation and autoimmunity.

Research paper thumbnail of Alternative p38 activation pathway mediated by T cell receptor–proximal tyrosine kinases

Nature Immunology, 2005

Signaling-responsive MAP kinases (MAPKs) are key in mediating immune responses and are activated ... more Signaling-responsive MAP kinases (MAPKs) are key in mediating immune responses and are activated through the phosphorylation of a Thr-X-Tyr motif by upstream MAPK kinases. Here we show that T cells stimulated through the T cell receptor (TCR) used an alternative mechanism in which p38 was phosphorylated on Tyr323 and subsequently autophosphorylated residues Thr180 and Tyr182. This required the TCR-proximal tyrosine kinase Zap70 but not the adaptor protein LAT, which was required for activation of extracellular signal-regulated protein kinase MAPKs. TCR activation of p38 lacking Tyr323 was diminished, and blocking of p38 activity prevented p38 dual phosphorylation in normal T cells but not in B cells. Thus, phosphorylation of Tyr323 dependent on the tyrosine kinase Lck and mediated by Zap70 serves as an important mechanism for TCR activation of p38 in T cells.

Research paper thumbnail of Gadd45a acts as a modifier locus for lymphoblastic lymphoma

Research paper thumbnail of Dimethylbenzanthracene Carcinogenesis in Gadd45a-null Mice Is Associated with Decreased DNA Repair and Increased Mutation Frequency

Mice lacking the Gadd45a gene are susceptible to ionizing radiationinduced tumors. Increased leve... more Mice lacking the Gadd45a gene are susceptible to ionizing radiationinduced tumors. Increased levels of Gadd45a transcript and protein are seen after treatment of cells with ionizing radiation as well as many other agents and treatments that damage DNA. Because cells deficient in Gadd45a were shown to have a partial defect in the global genomic repair component of the nucleotide excision repair pathway of UV-induced photoproducts, dimethylbenzanthracene (DMBA) carcinogenesis was investigated because this agent produces bulky adducts in DNA that are also repaired by nucleotide excision repair. Wild-type mice and mice deficient for Gadd45a were injected with a single i.p. dose of DMBA at 10 -14 days of age. The latency for spontaneous deaths was slightly decreased for Gadd45a-null mice compared with wild-type mice. At 17 months, all surviving animals were killed, and similar percentages of each genotype were found to have tumors. However, nearly twice as many Gadd45a-null than wild-type mice had multiple tumors, and three times as many had multiple malignant tumors. The predominant tumor types in wild-type mice were lymphoma and tumors of the intestines and liver. In Gadd45anull mice, there was a dramatic increase in female ovarian tumors, male hepatocellular tumors, and in vascular tumors in both sexes. In wild-type mice, this dose of DMBA induced a >5-fold increase in Gadd45a transcript in the spleen and ovary, whereas the increase in liver was >20-fold. Nucleotide excision repair, which repairs both UV-and DMBA-induced DNA lesions, was substantially reduced in Gadd45a-null lymphoblasts. Mutation frequency after DMBA treatment was threefold higher in Gadd45a-null liver compared with wild-type liver. Therefore, lack of basal and DMBA-induced Gadd45a may result in enhanced tumorigenesis because of decreased DNA repair and increased mutation frequency. Genomic instability, decreased cell cycle checkpoints, and partial loss of normal growth control in cells from Gadd45a-null mice may also contribute to this process.

Research paper thumbnail of Mice Lacking the p53Effector Gene Gadd45a Develop a Lupus-Like Syndrome

Immunity, 2002

Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stabil... more Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability and cell growth control. We have reported that one of the

Research paper thumbnail of The autoimmune suppressor Gadd45α inhibits the T cell alternative p38 activation pathway

Nature Immunology, 2005

The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have ... more The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have an alternative pathway in which T cell receptor-activated tyrosine kinase Zap70 phosphorylates p38 on Tyr323. Mice lacking Gadd45a, a small p38-binding molecule, develop a lupus-like autoimmune disease. Here we show that resting T cells but not B cells from Gadd45a À/À mice had spontaneously increased p38 activity in the absence of 'upstream' MAPK kinase activation. The p38 from resting Gadd45a À/À T cells was spontaneously phosphorylated on Tyr323, and its activity was specifically inhibited by recombinant Gadd45a in vitro. Thus, constitutive activation of T cell p38 through the alternative pathway is prevented by Gadd45a, the absence of which results in p38 activation, T cell hyperproliferation and autoimmunity.

Research paper thumbnail of Alternative p38 activation pathway mediated by T cell receptor–proximal tyrosine kinases

Nature Immunology, 2005

Signaling-responsive MAP kinases (MAPKs) are key in mediating immune responses and are activated ... more Signaling-responsive MAP kinases (MAPKs) are key in mediating immune responses and are activated through the phosphorylation of a Thr-X-Tyr motif by upstream MAPK kinases. Here we show that T cells stimulated through the T cell receptor (TCR) used an alternative mechanism in which p38 was phosphorylated on Tyr323 and subsequently autophosphorylated residues Thr180 and Tyr182. This required the TCR-proximal tyrosine kinase Zap70 but not the adaptor protein LAT, which was required for activation of extracellular signal-regulated protein kinase MAPKs. TCR activation of p38 lacking Tyr323 was diminished, and blocking of p38 activity prevented p38 dual phosphorylation in normal T cells but not in B cells. Thus, phosphorylation of Tyr323 dependent on the tyrosine kinase Lck and mediated by Zap70 serves as an important mechanism for TCR activation of p38 in T cells.

Research paper thumbnail of JESUS