Retinoic acid causes MEK-dependent RAF phosphorylation through RARα plus RXR activation in HL-60 cells

Hong, Hoang Thi Kim; Varvayanis, Susi; Yen, Andrew

doi:10.1046/j.1432-0436.2001.068001055.x

Cited by 47 publications

(55 citation statements)

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“…This confirmed that the 1,25D-induced phosphorylation was activating Raf-1 protein as an enzyme (Diaz et al, 1997;Xing and Kolesnick, 2001), rather than decreasing its kinase activity (Morrison et al, 1993;Dhillon et al, 2002), as shown in some other systems. This increase in the levels of phosphorylated Raf-1 was also observed when HL60 cells were exposed to all-trans RA at 1μM concentration, documented in previous studies to induce granulocytic differentiation of HL60 cells (Hong et al, 2001). However, in RA-treated cells the increase in P-Raf-1 was less marked (Fig.…”

Section: Resultssupporting

confidence: 85%

“…However, the increased Raf-1 activation in the later stages of differentiation was accompanied by decreased activation of MEK and ERK, suggesting that Raf-1 participates in 1,25D-induced monocytic differentiation by regulating other targets in this system, perhaps p90RSK. Thus, our data and reports in the literature (Porras et al, 1994;Kuo et al, 1996;Lenormand et al, 1996;Yen and Varvayanis, 2000;Hong et al, 2001;Akimov and Belkin, 2003;Dhillon et al, 2003) lead to the hypothesis that proliferative and prodifferentiation signals from active Raf-1 are channeled through different downstream targets.…”

supporting

confidence: 73%

“…Porras et al (1994) reported that there is a dissociation between the activation of Raf-1 and ERK2/p90RSK signaling of adipocytic differentiation of 3T3 L1 cells, and Lenormand et al (1996) showed that oncogenic Raf-1 activates p70S6K via a MAPK-independent pathway. Also, Kuo et al (1996) showed that Raf-1, but not MEK or ERK, is sufficient for differentiation of neuronal cells, while Yen et al found a disparity between the activation of Raf-1 and ERK by RA in HL60 cells, both as regards the timing (Hong et al, 2001), and the extent of activation (Yen and Varvayanis, 2000). Remarkably, it was also reported that the Raf oncogene and the MEK1/ERK signaling module have opposing roles in the regulation of surface transglutaminase in fibroblasts (Akimov and Belkin, 2003), while others described a Raf-1 mutant that disassociates MEK/ERK activation from differentiation but not from proliferation (Dhillon et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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Raf‐1 signaling is required for the later stages of 1,25‐dihydroxyvitamin D₃‐induced differentiation of HL60 cells but is not mediated by the MEK/ERK module

Wang

Studzinski

2006

Journal Cellular Physiology

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We are interested in determining the signaling pathways for 1,25-dihydroxyvitamin D 3 (1,25D)-induced differentiation of HL60 leukemic cells. One possible candidate is Raf-1, which is known to signal cell proliferation and neoplastic transformation through MEK, ERK, and downstream targets. It can also participate in the regulation of cell survival and various forms of cell differentiation, though the precise pathways are less well delineated. Here we report that Raf-1 has a role in monocytic differentiation of human myeloid leukemia HL60, which is not mediated by MEK and ERK, but likely by direct interaction with p90RSK. Specifically, we show that Raf-1 and p90RSK are increasingly activated in the later stages of differentiation of HL60 cells, at the same time as activation of MEK and ERK is decreasing. Transfection of a wild-type Raf-1 construct enhances 1,25D-induced differentiation, while antisense Raf-1 or short interfering (si) Raf-1 reduces 1,25D-induced differentiation. In contrast, antisense oligodeoxynucleotides (ODN) and siRNAs to MEK or ERK have no detectable effect on differentiation. In late stage differentiating cells Raf-1 and p90RSK are found as a complex, and inhibition of Raf-1, but not MEK or ERK expression reduces the levels of phosphorylatedp90RSK. These findings support the thesis that Raf-1 signals cell proliferation and cell differentiation through different intermediary proteins Involvement of mitogen-activated protein kinases (MAPKs) in signaling of monocyte/ macrophage differentiation induced by 1,25-dihydroxyvitamin D 3 (1,25D) has been well documented (e.g., Wang et al., 2000;Marcinkowska, 2001;Wang and Studzinski, 2001a;Kim et al., 2002;Studzinski et al., 2005), but the exact sequence of signaling steps has not been precisely elucidated. Early studies described MAPK activity as the basis of rapid, membranerelated effects of 1,25D on human acute promyelocytic leukemia NB4 cells (Song et al., 1998) and other cell types (Buitrago et al., 2006). These effects occurred in the time frame of seconds and minutes, but have not been universally observed in other cell types. More recently, studies in leukemia cells showed involvement of several more slowly activated MAPK cascades in signaling of 1,25D effects on cell proliferation (Wang and Studzinski, 2001a; Ji et al., 2002), survival (Wang andPepper et al., 2003;Zhang et al., 2006), and differentiation (Wang et al., 2000;Marcinkowska, 2001;Wang and Studzinski, 2001a;Studzinski et al., 2005). For instance, we and others have shown that in HL60 cells ERK1/2 is activated in the early phase of 1,25D-induced differentiation, and this can be accentuated by serum starving the cells prior to exposure to 1,25D (Marcinkowska et al., 1997;Marcinkowska, 2001;Wang and Studzinski, 2001a). Other studies have implicated JNK (Ji et al., 2002;Wang et al., 2003; Buitrago et al., 2006), p38 (Wang and Studzinski, 2001a,b;Ji et al., 2002) AKT (Zhang et al., 2006) pathways in the transmission of the 1,25D-generated signals to the transcriptional machi...

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Section: Resultssupporting

confidence: 85%

supporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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Raf‐1 signaling is required for the later stages of 1,25‐dihydroxyvitamin D₃‐induced differentiation of HL60 cells but is not mediated by the MEK/ERK module

Wang

Studzinski

2006

Journal Cellular Physiology

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“…Therefore, p38 MAPK may be considered as the main signaling protein mediating the pathway involved in expression of chemokine receptors. The results from prolonged ERK1/2 activation after 9CRA treatment indicate that ERK plays the role of an assistant on the expression of chemokine receptors, rather than inducing other biological effects due to 9CRA including cell differentiation and modulation of the cell cycle as demonstrated in previous reports (Hong et al, 2001;Yen et al, 2004).…”

Section: Discussionsupporting

confidence: 58%

p38 MAPK and ERK activation by 9-cis-retinoic acid induces chemokine receptors CCR1 and CCR2 expression in human monocytic THP-1 cells

Yun²,

Lee³

et al. 2007

Exp Mol Med

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9-cis-retinoic acid (9CRA) plays an important role in the immune response; this includes cytokine production and cell migration. We have previously demonstrated that 9CRA increases expression of chemokine receptors CCR1 and CCR2 in human monocytes. To better understand how 9CRA induces CCR1 and CCR2 expression, we examined the contribution of signaling proteins in human monocytic THP-1 cells. The mRNA and surface protein up-regulation of CCR1 and CCR2 in 9CRA-stimulated cells were weakly blocked by the pretreatment of SB202190, a p38 MAPK inhibitor, and PD98059, an upstream ERK inhibitor. Activation of p38 MAPK and ERK1/2 was induced in both a time and dose-dependent manner after 9CRA stimulation. Both p38 MAPK and ERK1/2 phosphorylation peaked at 2 h after a 100 nM 9CRA treatment. 9CRA increased calcium influx and chemotactic activity in response to CCR1-dependent chemokines, Lkn-1/CCL15, MIP-1α/CCL3, and RANTES/ CCL5, and the CCR2-specific chemokine, MCP-1/ CCL2. Both SB202190 and PD98059 pretreatment diminished the increased calcium mobilization and chemotactic ability due to 9CRA. SB202190 inhibited the expression and functional activities of CCR1 and CCR2 more effectively than did PD98059. Therefore, our results demonstrate that 9CRA transduces the signal through p38 MAPK and ERK1/2 for CCR1 and CCR2 up-regulation, and may regulate the pro-inflammatory process through the p38 MAPK and ERKdependent signaling pathways.

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“…103 It has been proposed that Raf-1 signaling may be activated in two stages: early in the differentiation process where its effects are mediated through activation of the MEK/ERK cascade and later during differentiation where its effects are mediated through p90 Rsk . 104,105 Activated Raf phosphorylates and activates the downstream kinases MEK-1 and MEK-2. 106 MEK-1 and MEK-2 are highly homologous, and are activated by phosphorylation by Raf on key serine residues (S217 and S221 of human MEK1).…”

Section: Raf/mek/erk Cascadementioning

confidence: 99%

Signal transduction pathways that contribute to myeloid differentiation

Miranda

Johnson

2007

Leukemia

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The production of mature, differentiated myeloid cells is regulated by the action of hematopoietic cytokines on progenitor cells in the bone marrow. Cytokines drive the process of myeloid differentiation by binding to specific cell-surface receptors in a stage-and lineage-specific manner. Following the binding of a cytokine to its cognate receptor, intracellular signal-transduction pathways become activated that facilitate the myeloid differentiation process. These intracellular signaling pathways may promote myelopoiesis by stimulating expansion of a progenitor pool, supporting cellular survival during the differentiation process, or by directly driving the phenotypic changes associated with differentiation. Ultimately, pathways that drive the differentiation process converge on myeloid transcription factors, including PU.1 and the C/EBP family, that are critical for differentiation to proceed. While much is known about the cytokines, cytokine receptors and transcription factors that regulate myeloid differentiation, less is known about the precise roles that specific signaling mediators play in promoting myeloid differentiation. Recently, however, the application of novel pharmacologic inhibitors, siRNA strategies, and transgenic and knockout models has begun to shed light on the involvement and function of signaling pathways in normal myeloid differentiation. This review will discuss the roles that key signaling pathways and mediators play in myeloid differentiation.

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Retinoic acid causes MEK-dependent RAF phosphorylation through RARα plus RXR activation in HL-60 cells

Cited by 47 publications

References 44 publications

Raf‐1 signaling is required for the later stages of 1,25‐dihydroxyvitamin D₃‐induced differentiation of HL60 cells but is not mediated by the MEK/ERK module

Raf‐1 signaling is required for the later stages of 1,25‐dihydroxyvitamin D₃‐induced differentiation of HL60 cells but is not mediated by the MEK/ERK module

p38 MAPK and ERK activation by 9-cis-retinoic acid induces chemokine receptors CCR1 and CCR2 expression in human monocytic THP-1 cells

Signal transduction pathways that contribute to myeloid differentiation

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Retinoic acid causes MEK-dependent RAF phosphorylation through RARα plus RXR activation in HL-60 cells

Cited by 47 publications

References 44 publications

Raf‐1 signaling is required for the later stages of 1,25‐dihydroxyvitamin D3‐induced differentiation of HL60 cells but is not mediated by the MEK/ERK module

Raf‐1 signaling is required for the later stages of 1,25‐dihydroxyvitamin D3‐induced differentiation of HL60 cells but is not mediated by the MEK/ERK module

p38 MAPK and ERK activation by 9-cis-retinoic acid induces chemokine receptors CCR1 and CCR2 expression in human monocytic THP-1 cells

Signal transduction pathways that contribute to myeloid differentiation

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Raf‐1 signaling is required for the later stages of 1,25‐dihydroxyvitamin D₃‐induced differentiation of HL60 cells but is not mediated by the MEK/ERK module

Raf‐1 signaling is required for the later stages of 1,25‐dihydroxyvitamin D₃‐induced differentiation of HL60 cells but is not mediated by the MEK/ERK module