The three major mitogen-activated protein kinases (MAPKs) p38, JNK, and ERK are signal transducers involved in a broad range of cell functions including survival, apoptosis, and cell differentiation. Whereas JNK and p38 have been generally linked to cell death and tumor suppression, ERK plays a prominent role in cell survival and tumor promotion, in response to a broad range of stimuli such as cytokines, growth factors, ultraviolet radiation, hypoxia, or pharmacological compounds. However, there is a growing body of evidence supporting that JNK and p38 also contribute to the development of a number of malignances. In this paper we focus on the involvement of the MAPK pathways in prostate cancer, including the less-known ERK5 pathway, as pro- or antitumor mediators, through their effects on apoptosis, survival, metastatic potential, and androgen-independent growth. 1. Introduction Mitogen-activated protein kinases (MAPKs) are serine/threonine kinases that mediate intracellular signaling associated with a variety of cellular activities including cell proliferation, differentiation, survival, death, and transformation [1, 2]. The three main members that integrate the MAPK family in mammalian cells are stress-activated protein kinase c-Jun NH2-terminal kinase (JNK), stress-activated protein kinase 2 (SAPK2, p38), and the extracellular signal-regulated protein kinases (ERK1/2, p44/p42) (Figure 1). In addition, other less-characterized MAPK pathways exist, such as the extracellular regulated kinase 5 (ERK5) pathway [3, 4] (Figure 1). Albeit with multiple exceptions, JNK and ERK5 are generally associated with apoptosis induction, while ERK1/2 are generally associated to mitogenesis, and inversely related to apoptosis [3, 4], and contradictory effects on cell death have been described to p38 [5–12]. Figure 1: Mitogen-activated protein kinase (MAPK) signaling. MAP kinases are activated by upstream kinases such as MAP kinase kinase (MAPKK), that include MEKs 1, 2, 3, 4, 5, 6, and 7. In turn, MAPKKs are activated by several different MAP kinase kinase kinases (MAPKKKs). Numerous stimulatory factors such as cytokines, mitogens, or death receptors can activate MAPKKKs. Each MAPK, depending on the stimulus and cell type, can phosphorylate different transcription factors. In mammalian cells, ERK, p38, and JNK activities are, respectively, regulated by different MAPKs cascades, which provide a link between transmembrane signaling and changes in transcription and that are activated in response to different environmental or developmental signals [4] (Figure 1). Depending
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