The Map Kinase Pathway

MAPKs are a group of enzymes that relay a variety of extracellular signals inside the cell (Chang and Karin, 2001). Three types of MAPKs are known, extracellular regulated kinases (ERKs), p38MAPK, and Jun N-terminal kinase (JNK). MAPKs are the terminal substrates of kinase cascades involving at least two other types of upstream kinases MAPKKKs and MAPKKs. The end result of this cascade is phosphorylation and activation of anyone of the three MAPKs mentioned above. ERKs are often associated with the transduction of mitotic signals generated by growth and survival factors (Shimada et al., 2006; Tibbles and Woodgett, 1999). JNK and p38MAPK mediate, among others, apoptotic signals generated by different types of cellular stresses (Beere, 2005; Bogoyevitch et al., 1996; Mehta and Miller, 1999; Ouyang et al., 2005; Roux and Blenis, 2004; Shen and Liu, 2006). In spite of these well-characterized effects, MAP kinases are involved in a panoply of cellular processes, including cytodifferentiation. The effects exerted by retinoids on MAPKs are multiple and an extensive discussion is beyond the scope of this chapter.

1. ERKs

The ERK pathway is known to be activated or inhibited by retinoids according to the specific cell context considered. In myeloid leukemia cells, such as HL-60, protracted activation of ERKs is believed to be necessary for the atRA-dependent granulocytic maturation and growth inhibition of the blast (Miranda et al., 2002; Wang and Studzinski, 2001; Yen et al., 1998, 1999). In fact, pharmacological inhibition of the ERK pathway suppresses the cytodifferentiating response of HL-60, NB4, and freshly isolated APL blasts to atRA (Miranda et al., 2002; Parrella et al., 2004; Wang and Studzinski, 2001; Yen et al., 1998, 1999). Activation of ERKs is also instrumental in inducing the differentiation of the mouse F9 teratocarcinoma cell along the primitive endoderm. However, further differentiation into parietal endodermal cells is hampered by ERK activation (Verheijen et al., 1999). Growth inhibition of breast carcinoma cells is accompanied and possibly mediated by atRA-dependent inhibition of the ERK pathway (Nakagawa et al., 2003). In neuroblastoma cells, ERKs do not seem to play any role in the process of neuronal differentiation activated by atRA (Miloso et al., 2004). At present, it is unclear whether the negative and positive actions of atRA on the ERK-signaling pathway require activation of the RXR/RAR complexes. This is possible in the case of the long-term activation of ERK in myeloid leukemia cells, while it is unlikely when atRA-triggered ERK phosphorylation and dephosphorylation events are rapid and require minutes to be completed. Though retinoids exert multiple effects on the ERK pathway, there is only one report demonstrating modulation of nuclear RARs' activity by this type of kinases. In T-cells, ERK induces the ligand-dependent transactivation of RXRs (Ishaq et al., 2000).

2. JNKs

AP-1 are transcriptional complexes whose principal components are homo- or heterodimers of the c-Fos/c-Jun type (Eferl and Wagner, 2003). The activation of AP-1 complexes is controlled by phosphorylation events triggered by JNK. AP-1 is involved in cellular responses to stress, cytokine, and proliferative stimuli (Karin and Shaulian, 2001). As already mentioned, ligand-bound RXR/RAR complexes have long been known to exert anti-AP-1 activity through a mechanism known as transrepression (Allenby, 1995; Fisher et al., 1998). More recently, the anti-AP-1 activity of retinoids has been associated with the ability of these compounds to inhibit JNK (Caelles et al., 1997; Gonzalez et al., 1999).

Given the importance of AP-1 complexes in the processes of cellular proliferation, it is not surprising that there is a relatively vast literature correlating the antiproliferative activity of retinoids with their inhibitory effects on JNK.

However, JNK inhibition by atRA has functional consequences not only for the proliferation but also for the differentiation of certain types of neoplastic cells. In AML, atRA reduces the basal level of JNK phosphorylation/activation and this effect may hinder the retinoid-dependent granulocytic maturation of the leukemia blast. The retinoid-potentiating agent ST1346 relieves the down-regulation of JNK afforded by atRA and stimulates retinoid-dependent granulocytic maturation. In addition, a specific JNK inhibitor blocks the enhancing effect of ST1346 on atRA-induced maturation of NB4 cells (Pisano et al., 2002).

JNK plays a central role in the process of cell differentiation activated by retinoids in embryocarcinoma, neuronal, and myeloid cells. In these cellular contexts, atRA stimulates rather than inhibit JNK phosphorylation and activation. Though the functional consequences are unknown, atRA has been reported to activate JNK also in head and neck squamous cell carcinoma (HNSCC). Interestingly, this effect is enhanced by cotreatment with 5-fluorouracil, a well-known chemotherapeutic agent, and correlated with the apoptotic responses induced by combinations of 5-fluorouracil and atRA (Masuda et al., 2002). Increased JNK activation was observed also in breast and prostate carcinoma cells. This phenomenon is associated with atRA-stimulated apoptotic responses to taxotere (Wang and Wieder, 2004).

JNK modulates the activity of nuclear RARs. In non-small cell lung carcinoma (NSCLC) cells, activation of JNK may be at the basis of the resistance to the action of retinoids (Lee et al., 1999). Activation of JNK contributes to RAR dysfunction by phosphorylating RARa and inducing degradation through the ubiquitin-proteasomal pathway. Interestingly, mice that develop lung cancer from activation of a latent K-ras oncogene have high intratumoral JNK activity, low RARa levels, and are resistant to treatment with RAR ligands. JNK inhibition in a human lung cancer cell line enhances RARa levels, ligand-induced activity of RXR-RAR dimers, and growth inhibition by atRA (Srinivas et al., 2005). In spite of these data, the major target of JNK activity seems to be the RXR moiety of the RAR/RXR complex. Overexpression and UV activation of JNK1 and JNK2 hyperphosphorylate mouse RXRa. This inducible hyperphosphorylation involves Ser61 and Ser75 as well as Thr87 in the B region and Ser265 in the ligand-binding domain (E region) (Adam-Stitah et al., 1999; Bour et al., 2005). Other serine residues in the A and C region of RXRa have been implicated in JNK-dependent hyperphosphorylation triggered by arsenic trioxide (Mann et al., 2005). The functional consequences of RXRa phos-phorylation by JNK are controversial. In one report, hyperphosphorylation by JNKs has been shown to exert no significant effect on the transactivation properties of either RXRa homodimers or RXRa/RARa heterodimers (Adam-Stitah et al., 1999). In two other reports, phosphorylation has been associated with inhibition of RXRa-mediated transcription (Bruck et al., 2005; Mann et al., 2005). At present, Ser32 in the A region or Ser265 in the

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