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Signal transduction pathways regulated by mitogen-activated/extracellular response kinase kinase kinase induce cell
N L Johnson1, A M Gardner, K M Diener
1Division of Basic Sciences, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206, USA.
Abstract:
Mitogen-activated/extracellular response kinase kinase (MEK) kinase (MEKK) is a serine-threonine kinase that regulates sequential protein phosphorylation pathways, leading to the activation of mitogen-activated protein kinases (MAPK), including members of the Jun kinase (JNK)/stress-activated protein kinase (SAPK) family. In Swiss 3T3 and REF52 fibroblasts, activated MEKK induces cell death involving cytoplasmic shrinkage, nuclear condensation, and DNA fragmentation characteristic of apoptosis. Expression of activated MEKK enhanced the apoptotic response to ultraviolet irradiation, indicating that MEKK-regulated pathways sensitize cells to apoptotic stimuli. Inducible expression of activated MEKK stimulated the transactivation of c-Myc and Elk-1. Activated Raf, the serine-threonine protein kinase that activates the ERK members of the MAPK family, stimulated Elk-1 transactivation but not c-Myc; expression of activated Raf does not induce any of the cellular changes associated with MEKK-mediated cell death. Thus, MEKK selectively regulates signal transduction pathways that contribute to the apoptotic response.
Insights
Mitogen-activated protein kinase kinase kinase (MEKK) triggers apoptosis and sensitizes cells to UV radiation. MEKK selectively activates specific signaling pathways, unlike Raf, highlighting its unique role in programmed cell death.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Mitogen-activated protein kinase kinase kinase (MEKK) is a key serine-threonine kinase.
- MEKK regulates sequential protein phosphorylation cascades, activating mitogen-activated protein kinases (MAPKs).
- MAPKs, including Jun kinase (JNK)/stress-activated protein kinase (SAPK) family members, are crucial in cellular signaling.
Purpose of the Study:
- To investigate the role of activated MEKK in inducing apoptosis.
- To determine if MEKK sensitizes cells to apoptotic stimuli like ultraviolet (UV) irradiation.
- To compare MEKK's signaling pathways with those of Raf kinase.
Main Methods:
- Expression of activated MEKK in Swiss 3T3 and REF52 fibroblasts.
- Observation of cellular changes indicative of apoptosis (cytoplasmic shrinkage, nuclear condensation, DNA fragmentation).
- Assessment of apoptotic response to UV irradiation in the presence of activated MEKK.
- Analysis of c-Myc and Elk-1 transactivation by activated MEKK and Raf.
Main Results:
- Activated MEKK induced apoptosis, characterized by distinct morphological and DNA fragmentation changes.
- MEKK expression enhanced the apoptotic response to UV irradiation, confirming sensitization to apoptotic stimuli.
- Activated MEKK stimulated transactivation of both c-Myc and Elk-1.
- Activated Raf stimulated Elk-1 transactivation but not c-Myc and did not induce apoptosis.
Conclusions:
- MEKK plays a critical role in initiating programmed cell death (apoptosis).
- MEKK-regulated pathways enhance cellular sensitivity to apoptotic triggers.
- MEKK exhibits selective regulation of signal transduction pathways distinct from Raf, contributing uniquely to the apoptotic response.