Review
The pathways to tumor suppression via route p38

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Besides its well-known functions in inflammation and other stresses, the p38 mitogen-activated protein kinase pathway also negatively regulates cell proliferation and tumorigenesis. Inactivation of the p38 pathway enhances cellular transformation and renders mice prone to tumor development with concurrent disruption of the induction of senescence. Conversely, persistent activation of p38 inhibits tumorigenesis. Mechanistic insights into this additional p38 function are starting to emerge. For example, p38 has been shown to have a crucial role in oncogene-induced senescence, replicative senescence, DNA-damage responses and contact-inhibition. In addition, the role of the p38 pathway in proliferative control and tumor suppression is mediated by its impact on several cell-cycle regulators. These findings reveal a tumor-suppressing function of the p38 pathway, and indicate that components of the p38 pathway are potential targets for novel cancer therapies.

Section snippets

The p38 pathway

The p38 pathway is one of the mitogen-activated protein kinase (MAPK) pathways [in addition to the extracellular signal-regulated kinase (ERK; see Glossary) and c-Jun N-terminal kinase (JNK) pathways]. The mammalian genome encodes four isoforms of p38 [p38 or p38α, p38β, p38γ and p38δ; also known as stress-activated protein kinase (SAPK) 2a, 2b, 3 and 4, respectively]. These isoforms differ in tissue distributions, regulation by upstream stimuli, and selectivity for upstream regulatory kinases

p38 and oncogene-induced senescence

In normal non-transformed cells, oncogene activation sometimes triggers senescence [13]. Like apoptosis, OIS is a tumor-suppressing defense mechanism that must be compromised for tumorigenesis to occur (Box 1). One type of well-characterized OIS is that induced by oncogenic ras genes (Box 2). Recent studies have revealed a major role of the p38 pathway in OIS caused by oncogenic ras or its downstream effector raf-1 that encodes a MAP3K 8, 14, 15, 16 (Figure 2). Ha-rasV12, which is an activated

p38 and replicative senescence

An important role of p38 in replicative senescence (Box 1) has been reported in primary human fibroblasts [15]. p38 is activated as a consequence of telomere-shortening when these cells undergo replicative senescence. Inactivation of p38, either by SB203580 treatment or ectopic expression of a dominant-negative mutant MKK6, delays the onset of replicative senescence and extends life span. However, cells with inactivated p38 are not completely immortalized, indicating that p38 is only

p38 and contact inhibition

Evasion of proliferative arrest induced by cell–cell contacts (i.e. contact inhibition) is one of the important features of tumorigenic cells. p38α has a crucial role in maintaining contact inhibition in non-transformed cells [34]. The kinase activity of p38α is persistently increased in confluent cultures of fibroblasts. Contact inhibition is impaired by SB203580 in human fibroblasts and in p38α−/− MEFs. Interestingly, the impairment of contact inhibition in p38α−/− MEFs leads to an increased

p38 and DNA-damage responses

In response to DNA damage, eukaryotic cells undergo proliferative arrest to enable DNA repair, which is important for maintaining genome stability and preventing tumorigenesis [36]. The p38 pathway has a prominent role in DNA-damage responses. p38 is activated by ionizing radiation [37] and, upon γ-irradiation, activation of MKK6 and p38γ by ataxia-telangiectasia mutated (ATM), a kinase regulating DNA-damage responses, is required for dividing cells to arrest at the G2–M-phase transition [38].

p38 and tumor suppression

The role of p38 MAPK in negative regulation of cell proliferation indicates that this pathway might be involved in the suppression of tumorigenesis. Indeed, accumulating evidence has revealed that inactivation of this pathway supports cellular transformation in vitro and promotes cancer development in mouse cancer models.

Animal models

Although deletion of p38α is embryonic lethal, recent studies in conditional knockout mice have revealed that p38α negatively regulates cell proliferation and tumorigenesis in vivo. In one study, p38α deficiency enhances proliferation of cells of multiple origins and promotes chemical-induced liver cancer development, correlating with upregulation of the JNK pathway [53]. Another study demonstrates that p38α deletion results in increased proliferation and defective differentiation of lung stem

Human cancer

Although comprehensive analysis of the integrity of p38 in human tumors has not been reported, several studies have begun to suggest that this pathway is disrupted in human cancer. A recent attempt to identify cancer-associated somatic mutations in protein kinase genes revealed that several components of the p38 pathway, including p38α, p38β and p38δ, are mutated in human tumors [60]. The expression of p38α is also downregulated in human lung tumors [54]. Consistent with its ability to suppress

Concluding remarks

Besides its well-known roles in inflammation and stress responses, recent studies have demonstrated an additional function of the p38 pathway in tumor suppression. The evidence comes from studies performed in cell culture and mouse-tumor models, in addition to limited data from analysis of human tumors. Different components of the p38 pathway participate in tumor suppression by controlling a variety of cellular responses such as OIS, replicative senescence, contact inhibition and DNA-damage

Glossary

7,12-dimethylbenzanthracene (DMBA)
an environmental mutagen that forms through the incomplete combustion of fossil fuel. It is commonly used as an initiator of carcinogenesis in mouse tumor models.
12-O-tetradecanoylphorbol-13-acetate (TPA)
an activator of the protein kinase C pathway. It is commonly used as a promoter of carcinogenesis in mouse tumor models.
14-3-3 proteins
a family of adaptor proteins that mediate signal transduction by binding to phosphoserine-containing proteins.
Ataxia

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