Muscle-specific roles for p38K MAP kinase in the regulation of locomotor activity in Drosophila Pubblico
del Rivero, Tania Paola (2010)
Abstract
p38K kinase (p38K) is a member of the well-studied MAP Kinase family of protein kinases that are involved in a variety of cellular signaling pathways and are capable of regulating gene expression. The p38K kinase in particular, belongs to a subfamily of MAP kinases known as the SAPKs (stress activated protein kinases) which are involved in the stress response. p38K is activated by a number of extracellular stressors, such as the reactive oxygen species (ROS) released by oxidative stress. This type of stress leads to mitochondrial dysfunction and apoptotic death in many cell types (e.g. Parkinson's Disease patients are particularly vulnerable to its effects). Although p38K is a bona fide stress responsive signaling protein, cellular targets of p38K signaling in the context of stress and in vivo roles for p38K in stress regulation remain unknown.
Recently, the Sanyal lab has studied the function of p38K in Drosophila using a double knockout model consisting of null mutations in both p38K Drosophila homologs: p38a and p38b. The p38K double knockouts exhibit a reduced lifespan, increased sensitivity to oxidative stress, and locomotor dysfunction. While these findings show how a general lack of p38K can impair locomotor ability, they do not specify what cell types require p38K for normal locomotor function. The aim of the current study was to identify these p38K-dependent cell types by using the GAL4-UAS system to selectively inhibit p38K in specific tissues. Using this system, we were able to test the effects of inhibiting p38K (using a dominant-negative p38K transgenic protein) in distinct cell types on locomotor function. Here, we not only find that locomotor deficits result from overexpressing the dominant-negative form of p38b in all cell types, but also that these deficits are observed when p38K is solely inhibited in muscle cells. We predict that this locomotor impairment may be caused by an increase in oxidative stress-related damage in the muscles resulting from the disruption of the p38K signaling pathway.
Table of Contents
Table of Contents
Introduction………………………………………………………………………….……1
MAP
Kinases……………………………………………………………………………...1
Figure
1…………………………………………………………………………………....2
p38K and the Oxidative Stress
Response………………………………………………....3
Parkinson's Disease and
ROS……………………………………………………………..4
Parkin and p38K in
Drosophila…………………………………………………………...6
Targeted Overexpression of
p38bKD……………………………………………………..7
Figure
2……………………………………………………………………………………8
Results: Part
A………………………………………………………………………...…10
Figure
3……………………………………………………………………………….….11
Figure
4………………………………………………………………………………..…12
Figure
5a……………………………………………………………………………..…..13
Figure
5b………………………………………………………………………………....13
Figure
6…………………………………………………………………………………..13
Methods……………………………………………………………………………..........14
Results: Part
B...…………………………………………………………………………17
Figure
7a…………………………………………………………………………………17
Figure
7b…………………………………………………………………………………17
Overall p38K Inhibition Leads to Locomotor
Deficits…………………………………..17
Figure
8a…………………………………………………………………………………19
Figure
8b…………………………………………………………………………………19
P38K Inhibition in Motor Neurons Does Not Impair Locomotor
Activity……………...20
Figure
9…………………………………………………………………………………..22
P38K Inhibition in Muscle Tissue Impairs Locomotor
Function………………………..22
Discussion………………………………………………………………………………24
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