ArticleThe Journal of experimental medicine2001
The stress kinase mitogen-activated protein kinase kinase (MKK)7 is a negative regulator of antigen receptor and growth factor receptor-induced proliferation in hematopoietic cells.
Article in The Journal of experimental medicine, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 63 citations in OpenAlex.
- Off-Target MAP2K7 Inhibition Drives the Antileukemic Activity of the PD-1/PD-L1 inhibitor ACS-69 in Pediatric T-ALL.Research square · 2026Article
- Targeting the JNK Gatekeepers: Structural Evolution and Medicinal Chemistry of MKK4 and MKK7 Inhibitors.Molecules (Basel, Switzerland) · 2026Review
- Time-series transcriptomic analysis of Nile tilapia reveals the crucial roles of long non-coding RNA and transcription factor in response to Aeromonas veronii infection.BMC genomics · 2025Article
- Pharmacological inhibition of the MAP2K7 kinase in human disease.Frontiers in oncology · 2024Review
- The schizophrenia risk gene Map2k7 regulates responding in a novel contingency-shifting rodent touchscreen gambling task.Disease models & mechanisms · 2022Article
- Inhibition of the MAP2K7-JNK pathway with 5Z-7-oxozeaenol induces apoptosis in T-cell acute lymphoblastic leukemia.Oncotarget · 2021Article
- The role of MKK4 in T-cell development and immunity to viral infections.Immunology and cell biology · 2021Article
- Restriction of memory B cell differentiation at the germinal center B cell positive selection stage.The Journal of experimental medicine · 2020Article
- Map2k7 Haploinsufficiency Induces Brain Imaging Endophenotypes and Behavioral Phenotypes Relevant to Schizophrenia.Schizophrenia bulletin · 2020Article
- JNK signalling mediates aspects of maternal immune activation: importance of maternal genotype in relation to schizophrenia risk.Journal of neuroinflammation · 2019Article
- Novel tumor-suppressor function of KLF4 in pediatric T-cell acute lymphoblastic leukemia.Experimental hematology · 2017Review
- Article
- The MKK7 p.Glu116Lys Rare Variant Serves as a Predictor for Lung Cancer Risk and Prognosis in Chinese.PLoS genetics · 2016Article
- Widespread JNK-dependent alternative splicing induces a positive feedback loop through CELF2-mediated regulation of MKK7 during T-cell activation.Genes & development · 2015Article
- Regulation of monocyte differentiation by specific signaling modules and associated transcription factor networks.Cellular and molecular life sciences : CMLS · 2014Review
- Article
- Regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-Jun N-terminal kinase pathway.Arthritis research & therapy · 2012Article
- Distinct signaling properties of mitogen-activated protein kinase kinases 4 (MKK4) and 7 (MKK7) in embryonic stem cell (ESC) differentiation.The Journal of biological chemistry · 2012Article
- Frailty, inflammation, and immunity.Aging and disease · 2011Article
- Inflammation and immune system alterations in frailty.Clinics in geriatric medicine · 2011Article
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Authors and funding
16 authors at 6 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The dual specificity kinases mitogen-activated protein kinase (MAPK) kinase (MKK)7 and MKK4 are the only molecules known to directly activate the stress kinases stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinases (JNKs) in response to environmental or mitogenic stimuli. To examine the physiological role of MKK7 in hematopoietic cells, we used a gene targeting strategy to mutate MKK7 in murine T and B cells and non-lymphoid mast cells. Loss of MKK7 in thymocytes and mature B cells results in hyperproliferation in response to growth factor and antigen receptor stimulation and increased thymic cellularity. Mutation of mkk7 in mast cells resulted in hyperproliferation in response to the cytokines interleukin (IL)-3 and stem cell factor (SCF). SAPK/JNK activation was completely abolished in the absence of MKK7, even though expression of MKK4 was strongly upregulated in mkk7(-/-) mast cell lines, and phosphorylation of MKK4 occurred normally in response to multiple stress stimuli. Loss of MKK7 did not affect activation of extracellular signal-regulated kinase (ERK)1/2 or p38 MAPK. mkk7(-/-) mast cells display reduced expression of JunB and the cell cycle inhibitor p16INK4a and upregulation of cyclinD1. Reexpression of p16INK4a in mkk7(-/-) mast cells abrogates the hyperproliferative response. Apoptotic responses to a variety of stimuli were not affected. Thus, MKK7 is an essential and specific regulator of stress-induced SAPK/JNK activation in mast cells and MKK7 negatively regulates growth factor and antigen receptor-driven proliferation in hematopoietic cells. These results indicate that the MKK7-regulated stress signaling pathway can function as negative regulator of cell growth in multiple hematopoietic lineages.
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