Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the role of Smad family proteins, known to be important cytoplasmic mediators of signals from the transforming growth factor-beta (TGF-beta) receptor serine/threonine kinases, in TGF-beta-dependent differentiation of hematopoietic cells, using as a model the human promyelocytic leukemia cell line, HL-60. TGF-beta-dependent differentiation of these cells to monocytes, but not retinoic acid-dependent differentiation to granulocytes, was accompanied by rapid phosphorylation and nuclear translocation of Smad2 and Smad3. Vitamin D(3) also induced phosphorylation of Smad2/3 and monocytic differentiation; however the effects were indirect, dependent on its ability to induce expression of TGF-beta1. Simultaneous treatment of these cells with TGF-beta1 and all-trans-retinoic acid (ATRA), which leads to almost equal numbers of granulocytes and monocytes, significantly reduced the level of phospho-Smad2/3 and its nuclear accumulation, compared with that in cells treated with TGF-beta1 alone. TGF-beta1 and ATRA activate P42/44 mitogen-activated protein (MAP) kinase with nearly identical kinetics, ruling out its involvement in these effects on Smad phosphorylation. Addition of the inhibitor-of-protein serine/threonine phosphatases, okadaic acid, blocks the ATRA-mediated reduction in TGF-beta-induced phospho-Smad2 and shifts the differentiation toward monocytic end points. In HL-60R mutant cells, which harbor a defective retinoic acid receptor-alpha (RAR-alpha), ATRA is unable to reduce levels of TGF-beta-induced phospho-Smad2/3, coincident with its inability to differentiate these cells along granulocytic pathways. Together, these data suggest a new level of cross-talk between ATRA and TGF-beta, whereby a putative RAR-alpha-dependent phosphatase activity limits the levels of phospho-Smad2/3 induced by TGF-beta, ultimately reducing the levels of nuclear Smad complexes mediating the TGF-beta-dependent differentiation of the cells to monocytic end points.
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PMID:Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-beta and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells. 1239 16

The evidence for the promising potential for derivatives of Vitamin D (deltanoids) in the treatment of myeloid leukemias is increasing, but currently is not matched by the understanding of the precise mechanisms by which these anti-neoplastic effects are achieved. Unlike solid tumors in which growth retardation by deltanoids appears to result from inhibition of cell proliferation and the promotion of cell death by apoptosis, control of myeloid leukemia proliferation by deltanoids results from the induction of differentiation of the immature myelo-monocytic cells towards functional monocytic cells. We present here the accumulating evidence that a pathway that is initiated by deltanoid activation of Vitamin D receptor (VDR) and leads to monocytic differentiation of human myeloblastic HL60 cells, includes the MEK-ERK and JNK mitogen-activated protein kinases (MAPKs), their positive and negative regulators and a downstream effector C/EBPbeta. As in other cells, the abundance of VDR protein increases shortly after an exposure of HL60 cells to 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2) D(3)). Other early events include a parallel upregulation of kinase suppressor of Ras (KSR-1) and the activation of the ERK MAPK pathway and data suggest that KSR-1 acts to amplify the signal provided by low concentrations of 1alpha,25(OH)(2) D(3). Maintenance of monocytic differentiation may be enhanced by JNK, but diminished by p38, MAPK signaling. Downstream, one of the targets of these pathways is C/EBPbeta, which can directly interact with the promoter for CD14, a gene characteristically expressed in monocytes. Importantly, in freshly obtained acute myeloid leukemia (AML)-M2 cells exposed to PRI-2191, a novel deltanoid with a modified side chain, upregulation of C/EBPbeta paralleled the induction of monocytic differentiation. These data provide a basis for the hypothesis that deltanoid-induced upregulation of C/EBPbeta bypasses the block to granulocytic differentiation in myeloid leukemia cells by redirecting the cells to monocytic differentiation.
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PMID:The rationale for deltanoids in therapy for myeloid leukemia: role of KSR-MAPK-C/EBP pathway. 1604 62

In intestinal cells, as in other target cells, the steroid hormone 1alpha,25(OH)(2)-Vitamin D(3) (1alpha,25(OH)(2)D(3)) regulates gene expression via the specific intracellular Vitamin D receptor and induces fast non-transcriptional responses involving stimulation of transmembrane signal transduction pathways. We have previously shown that the hormone activates the extracellular signal-regulated mitogen-activated protein (MAP) kinase isoforms ERK1 and ERK2 in rat intestinal cells. In the present study, we have demonstrated that 1alpha,25(OH)(2)D(3) also induces the phosphorylation and activation of p38 MAPK in these cells. The hormone effects were time and dose-dependent, with maximal stimulation at 2min (+3-fold) and 1nM. 1alpha,25(OH)(2)D(3)-dependent p38 phosphorylation was suppressed by SB 203580, a selective inhibitor of p38 MAPK. Ca(2+) chelation with EGTA, inhibition of the c-Src-tyrosine kinase family with PP1 or protein kinase A (PKA) with Rp-cAMP, attenuated hormone activation of p38 MAPK. The physiological significance of 1alpha,25(OH)(2)D(3)-dependent activation of ERK1/2 and p38 MAP kinases was addressed by monitoring c-Fos expression. Incubation of intestinal cells with the hormone was followed by a rapid induction of c-Fos expression which was blocked by SB 203580 and partially suppressed by the ERK1/2 inhibitor PD 98059. Our results suggest that 1alpha,25(OH)(2)D(3) activates p38 MAPK, involving Ca(2+), c-Src and PKA as upstream regulators, and that p38 MAPK has a central role in hormone-induction of the oncoprotein c-Fos in rat intestinal cells.
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PMID:1alpha,25(OH)(2)-Vitamin D(3) stimulates intestinal cell p38 MAPK activity and increases c-Fos expression. 1648 31