p38 MAPK

p38 MAPK is implicated in a number of pathologies, including cancer, cardiovascular dysfunction and, Alzheimer’s Disease [1][2].

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The role of p38 MAPK pathway in cancer development has been the subject of intense research over the past three decades. The negative regulation of proliferation by p38α (through downregulating cyclins, upregulating cyclin-dependent kinase (CDK) inhibitors and modulating the tumour suppressor p53) has been identified as a highly conserved function of the alpha subunit in a number of cells including lung cells and fibroblasts [3]. This effect of p38α is thought to be mediated by JNK/JUN pathway and EGFR downregulation (Figure 1). However, this has been contradicted by other studies suggesting p38α, in fact, can positively regulate proliferation and contribute towards apoptosis resistance in cancer cells, possibly due to antagonisation of DNA damage induced by chemotherapy [3]. The positive regulation of proliferation may be inhibited after treatment with p38α inhibitors, or killing cancer cells through damaging p38α-mediated cell cycle arrest and DNA repair mechanisms, as a result of DNA-damaging chemotherapy [3]. Phosphorylated p38α has also been linked to malignant growths in cancers, including follicular lymphoma and breast carcinomas [2].

 

Aside from cancer development, p38 MAPK has also been implicated in resistance to cancer therapies [1]. In colon cancer treatment, p38 MAPK has been found to confer resistance against drugs including cisplatin, irinotecan and 5-fluorouracil.1]. One approach to combating this issue is to use combination therapy, such as sorafenib and a p38α MAPK inhibitor, for treating heptatocellular carcinoma [1]. Without the p38α inhibitor, p38α MAPK would be able to confer resistance to sorafenib through activation of the MEK-ERK-ATF2 [MM1] signalling axis [1], reducing the effectiveness of the treatment.

 

Cardiovascular Dysfunction

 

In addition to cancer, some studies have suggested that p38 MAPKs may be associated with cardiovascular dysfunction. p38α has been identified as the dominant isoform of p38 MAPK in the heart [3], and an association between p38α activity and the promotion of apoptosis has been hypothesised[2]. Further evidence for p38α contributing to apoptosis has been demonstrated through studies in which hypoxic induced apoptosis caused by ischemia reperfusion was greatly reduced by inhibition of p38α [2]. However, p38α can help protect against stress-induced apoptosis after a myocardial infarction, through the activation of p38α MAPK-MAPKAP-K2, which phosphorylates aB-crystallin (a small heat shock protein) [2].

 

Alzheimer's Disease

 

Finally p38α MAPK may play a crucial role in Alzheimer’s disease development. The presence of oxidative stress in the brain is a notable marker of Alzheimer’s Disease, This oxidative stress is thought to activate p38 MAPK, resulting in the hyperphosphorylation of tau, a protein that mediates axonal transport in the brain [1][4]. Hyperphosphorylation of tau however disrupts its function and leads to the accumulation of neurofibrillary triangles within the brain [4} . This process is induced by Ab[MM2] , and leads to neuroinflammation[MM3] , which is characteristic of Alzheimer’s disease [1]. Possible treatments for treating Alzheimer’s disease include inhibiting Interleukin-1 b signalling (IL-1b signalling) using an antibody complementary to the IL-1 receptor, which has been shown to be effective at treating cognitive defects associated with Alzheimer’s Disease in transgenic mice [1]. p38 inhibitors have also been shown to reduce Ab plaque load [1].

 

References

 

1. Kim EK, Choi E-J. Compromised MAPK signaling in human diseases: an update. Arch Toxicol. 2015;89(6):867–82.

http://www.ncbi.nlm.nih.gov/pubmed/25690731

2. Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 2007;1773:1358–75.

http://www.ncbi.nlm.nih.gov/pubmed/17481747

3. Wagner EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer.

http://www.ncbi.nlm.nih.gov/pubmed/19629069

4. LaFerla FM, Green KN, Oddo S. Intracellular amyloid-β in Alzheimer’s disease. Nat Rev Neurosci. 2007;8(7):499–509.

http://www.ncbi.nlm.nih.gov/pubmed/17551515