Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of mouse embryonic day 13.5 and 15.5 fetal livers lacking p38alpha, a mitogen-activated kinase that controls inflammatory responses and cell proliferation

ABSTRACT: The mitogen-activated protein kinase (MAPK) p38alpha controls inflammatory responses and cell proliferation. Using mice carrying conditional p38alpha alleles, we investigated its function in postnatal development and tumorigenesis. When p38alpha is specifically deleted in the mouse embryo, fetuses develop to term but die shortly after birth, likely due to lung dysfunction. Fetal hematopoietic cells and embryonic fibroblasts deficient in p38alpha display increased proliferation, resulting from sustained activation of the c-Jun N-terminal kinase (JNK)/c-Jun pathway. Importantly, in chemical-induced liver cancer development, mice with liver-specific deletion of p38alpha show enhanced hepatocyte proliferation and tumor development that also correlates with JNK/c-Jun upregulation. Furthermore, increased proliferation of p38alpha-deficient hepatocytes and tumor cells is suppressed by inactivation of JNK or c-Jun. These results reveal a novel mechanism whereby p38alpha negatively regulates cell proliferation through antagonizing the JNK/c-Jun pathway in multiple cell types and in liver cancer development. We used microarrays to identifiy differental regulated genes by p38alpha in fetal liver cells Experiment Overall Design: Wild type and p38 deficient fetal liver cell were used for RNA extraction and hybridization on Affymetrix microarrays.

ORGANISM(S): Mus musculus

SUBMITTER: Norbert Schweifer

PROVIDER: E-GEOD-7342 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway.

Hui Lijian L Bakiri Latifa L Mairhorfer Andreas A Schweifer Norbert N Haslinger Christian C Kenner Lukas L Komnenovic Vukoslav V Scheuch Harald H Beug Hartmut H Wagner Erwin F EF

Nature genetics 20070429 6

The mitogen-activated protein kinase (MAPK) p38alpha controls inflammatory responses and cell proliferation. Using mice carrying conditional Mapk14 (also known as p38alpha) alleles, we investigated its function in postnatal development and tumorigenesis. When we specifically deleted Mapk14 in the mouse embryo, fetuses developed to term but died shortly after birth, probably owing to lung dysfunction. Fetal hematopoietic cells and embryonic fibroblasts deficient in p38alpha showed increased proli ...[more]

PMID: 17468757

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Project description:BACKGROUND & AIMS: c-Jun N-terminal kinase (JNK)1 and JNK2 are expressed in hepatocytes and have overlapping and distinct functions. JNK proteins are activated, via phosphorylation, in response to acetaminophen- or CCl4-induced liver damage; the level of activation correlates with the degree of injury. SP600125, a JNK inhibitor, has been reported to block acetaminophen-induced liver injury. We investigated the role of JNK in drug-induced liver injury (DILI) in liver tissues from patients and in mice with genetic deletion of JNK in hepatocytes. METHODS: We studied liver sections from patients with DILI (due to acetaminophen, phenprocoumon, non-steroidal anti-inflammatory drugs or autoimmune hepatitis), or patients without acute liver failure (controls), collected from a DILI Biobank in Germany. Levels of total and activated (phosphorylated) JNK were measured by immunohistochemistry and western blotting. Mice with hepatocyte-specific deletion of Jnk1 (Jnk1Îhepa) or combination of Jnk1 and Jnk2 (JnkÎhepa), as well as Jnk1-floxed C57BL/6 (control) mice, were given injections of CCl4 (to induce fibrosis) or acetaminophen (to induce toxic liver injury). We performed gene expression microarray, and phosphoproteomic analyses to determine mechanisms of JNK activity in hepatocytes. RESULTS: Liver samples from DILI patients contained more activated JNK, predominantly in nuclei of hepatocytes and in immune cells, than healthy tissue. Administration of acetaminophen to JnkÎhepa mice produced a greater level of liver injury than that observed in Jnk1Îhepa or control mice, based on levels of serum markers and microscopic and histologic analysis of liver tissues. Administration of CCl4 also induced stronger hepatic injury in JnkÎhepa mice, based on increased inflammation, cell proliferation, and fibrosis progression, compared to Jnk1Îhepa or control mice. Hepatocytes from JnkÎhepa mice given acetaminophen had an increased oxidative stress response, leading to decreased activation of AMPK, total protein AMPK levels, and pJunD and subsequent necrosis. Administration of SP600125 before or with acetaminophen protected JnkÎhepa and control mice from liver injury. CONCLUSIONS: In hepatocytes, JNK1 and JNK2 appear to have combined effects in protecting mice from CCl4- and acetaminophen-induced liver injury. It is important to study the tissue-specific functions of both proteins, rather than just JNK1, in the onset of toxic liver injury. JNK inhibition with SP600125 shows off-target effects. Livers and primary hepatocytes were isolated from wild type and JNKÎhepa (Jnk1Îhepa/global Jnk2-/-) double-knockout mice and subjected to gene expression profiling.

Project description:BACKGROUND & AIMS: c-Jun N-terminal kinase (JNK)1 and JNK2 are expressed in hepatocytes and have overlapping and distinct functions. JNK proteins are activated, via phosphorylation, in response to acetaminophen- or CCl4-induced liver damage; the level of activation correlates with the degree of injury. SP600125, a JNK inhibitor, has been reported to block acetaminophen-induced liver injury. We investigated the role of JNK in drug-induced liver injury (DILI) in liver tissues from patients and in mice with genetic deletion of JNK in hepatocytes. METHODS: We studied liver sections from patients with DILI (due to acetaminophen, phenprocoumon, non-steroidal anti-inflammatory drugs or autoimmune hepatitis), or patients without acute liver failure (controls), collected from a DILI Biobank in Germany. Levels of total and activated (phosphorylated) JNK were measured by immunohistochemistry and western blotting. Mice with hepatocyte-specific deletion of Jnk1 (Jnk1Δhepa) or combination of Jnk1 and Jnk2 (JnkΔhepa), as well as Jnk1-floxed C57BL/6 (control) mice, were given injections of CCl4 (to induce fibrosis) or acetaminophen (to induce toxic liver injury). We performed gene expression microarray, and phosphoproteomic analyses to determine mechanisms of JNK activity in hepatocytes. RESULTS: Liver samples from DILI patients contained more activated JNK, predominantly in nuclei of hepatocytes and in immune cells, than healthy tissue. Administration of acetaminophen to JnkΔhepa mice produced a greater level of liver injury than that observed in Jnk1Δhepa or control mice, based on levels of serum markers and microscopic and histologic analysis of liver tissues. Administration of CCl4 also induced stronger hepatic injury in JnkΔhepa mice, based on increased inflammation, cell proliferation, and fibrosis progression, compared to Jnk1Δhepa or control mice. Hepatocytes from JnkΔhepa mice given acetaminophen had an increased oxidative stress response, leading to decreased activation of AMPK, total protein AMPK levels, and pJunD and subsequent necrosis. Administration of SP600125 before or with acetaminophen protected JnkΔhepa and control mice from liver injury. CONCLUSIONS: In hepatocytes, JNK1 and JNK2 appear to have combined effects in protecting mice from CCl4- and acetaminophen-induced liver injury. It is important to study the tissue-specific functions of both proteins, rather than just JNK1, in the onset of toxic liver injury. JNK inhibition with SP600125 shows off-target effects.

Dataset Information

Transcription profiling of mouse embryonic day 13.5 and 15.5 fetal livers lacking p38alpha, a mitogen-activated kinase that controls inflammatory responses and cell proliferation

Publications

p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway.

Similar Datasets

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