p38α: A Suppressor of Cell Proliferation and Tumorigenesis

Abstract

The mitogen-activated protein kinase (MAPK) p38α is involved in numerous biological processes and is a drug target for inflammation-associated diseases. Genetic analysis in mice demonstrated that fetuses lacking p38α are embryonic lethal owing to impaired placental development. The function of p38α in mice after birth remained unclear until conditional alleles of p38α were used. It was found that p38α is essential for lung function in both neonatal and adult mice. Increased proliferation and impaired differentiation are the hallmarks of p38α-deficient cells. Moreover, mice deficient in p38α are prone to cancer development using carcinogen or oncogene-induced cancer models. p38α can suppress cell proliferation by antagonizing the JNK/c-Jun pathway, which is an important regulator of proliferation and apoptosis. These findings suggest that therapeutic inhibition of p38 might lead to unwanted proliferation. Therefore, a combined inhibition of p38 and other pathways, such as the JNK pathway, should be considered for targeting cancer inflammation.

Separate Cyclic AMP Sensors for Neuritogenesis, Growth Arrest, and Survival of Neuroendocrine Cells

“…In fact, the Epacs have been reported to both positively and negatively affect cell cycle entry and exit, depending on the cell type and relative expression levels of Epac1 and Epac2 (47). P38 activation has been shown to exert antiproliferative effects in many cell and tissue types, including tumors in skin, lung, and liver (48), and p38 hypoactivity has been noted in human tumors (32). In this study, Epac-dependent activation of the p38 pathway was shown to be necessary for growth arrest of NS-1 pheochromocytoma cells, and, therefore, it is possible that Epac/p38 signaling may play an inhibitory role in the development of neuroendocrine tumors.…”

MAPK signaling in inflammation-associated cancer development

“…The p38α and p38β isoforms are widely expressed in most tissues, while p38g and p38d are more strictly expressed in muscle, skin, and kidney cells (Han and Sun, 2007;Hui et al, 2007b). Loss of p38 causes embryonic lethality between embryonic day 10.5 and 16.5 in mice.…”

“…Mice with disruption of other p38 isoforms are viable and fertile. Recently, it was reported that mice lacking p38g showed defects in insulin secretion in pancreatic β cells (Sumara et al, 2009). p38α is a serine/threonine kinase which rapidly responds to stresses such as endotoxic lipopolysaccharide (LPS) and heat shock (Han and Sun, 2007;Hui et al, 2007b). p38α phosphorylation is regulated by MKK3 and MKK6, which are activated by upstream kinases, such as MTK1 and ASK1 (Han and Sun, 2007;Hui et al, 2007b).…”

“…Alternatively, p38α can be activated by a MAPK kinase independent mechanism mediated by TAB1 (Ge et al, 2002). Downstream targets of p38α include protein kinases such as MK2 and PRAK (MK5), and transcription factors such as ATF2 and Mitf (Han and Sun, 2007;Hui et al, 2007b).…”

“…Apart from its role in sensing stress signals, recent data also revealed that p38α plays a pivotal role in cell cycle transition and cell differentiation (Han and Sun, 2007;Hui et al, 2007b;Wagner and Nebreda, 2009). p38α-deficient MEFs proliferate faster and exhibit delayed senescence compared to control cells, due to the increased G1/S and G2/ M transitions by upregulation of cyclin D1 and inactivation of p53 activity (Hui et al, 2007a;Sun et al, 2007).…”