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)

Protein phosphatases have been classified into two basic types, namely protein serine/threonine phosphatase (PP), and protein tyrosine phosphatase (PTP). Cpd 5 is a selective inhibitor of cdc25 phosphatases, which belong to members of PTPs and regulate cell proliferation by controlling cyclin-dependent kinases (cdks). The present study was undertaken to investigate the potential utility of Cpd 5 as an anti-neoplastic agent for renal cell carcinomas (RCCs). Three renal cancer cell lines, 769P, Sw839, and A498 were used. The effects of Cpd 5 on the viability of renal cancer cell lines was analyzed using an Alamar Blue assay. Apoptosis was determined by flow cytometric TUNEL analysis. Changes in the expression of cdc25 phosphatases, mitogen-activated protein kinases (MAPKs), and bcl-2 family proteins were detected using Western blot analysis. The apoptosis-inducing effect of Cpd 5 on human RCC tissue was analyzed through TUNEL staining of organ cultures from RCCs. Cpd 5 showed a strong cytotoxicity against all renal cancer cell lines with an apoptosis-inducing effect. All cell lines treated with Cpd 5 resulted in a down-regulation of cdc25A, cdc25B, and cdc25C, however, the MAPK pathways were not affected. In addition, the up-regulation of bax, and the down-regulation of bcl-2 and bcl-xL, was observed. In organ cultures from RCCs, TUNEL-positive apoptotic nuclei were observed when treated with Cpd 5. Cpd 5 was thus found to effectively inhibit the proliferation of human renal cancer cells while also inducing apoptosis by inhibiting cdc25 phosphatases and modulating bcl-2 family proteins. The administration of Cpd 5 may thus be an effective therapeutic approach for RCCs.
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PMID:Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells. 1607 67

Angiotensin II (ANG II) induces cell-cycle arrest of cultured proximal tubular cells, resulting in cellular hypertrophy. This ANG II-mediated hypertrophy is associated with the induction of p27(Kip1), an inhibitor of G1 phase cyclin-dependent kinase cyclin complexes. We have recently demonstrated that ANG II-mediated expression of p27(Kip1) and induction of cellular hypertrophy depend on the generation of reactive oxygen species (ROS). The effects of ROS are mediated by stimulation of mitogen-activated protein (MAP) kinases. p44/42 MAP kinase directly phosphorylates p27(Kip1) at serine-threonine residues and increases thereby its half-life time. AT2-receptor activation has been implicated in apoptosis and/or cell differentiation. Recent studies, however, revealed a more indirect role of hypoxia in the antiproliferative effects of ANG II transduced through AT2 receptors. We found that SM-20 is down-regulated in ANG II-stimulated PC12 cells that express only AT2 receptors. It turned out that SM20 is the rat homologue of a dioxygenase that regulates hypoxia-inducible factor 1 (HIF-1). ANG II induces HIF-1alpha by a posttranscriptional mechanism suggesting that SM20 down-regulation leads to stabilization of HIF-1. Thus, ANG II-induced ROS generation plays a pivotal role in several pathophysiological situations, leading to renal growth regulation and remodeling after injury.
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PMID:Role of reactive oxygen species in angiotensin II-mediated renal growth, differentiation, and apoptosis. 1611 39

Prostate cancer cells rely on androgen receptor (AR) for proliferation and survival. Therefore, curing prostate cancer will require elimination of AR. Although androgen is the natural ligand that activates AR, AR activity is also subject to regulation by growth factor/growth factor receptor-stimulated signaling pathways that control the cell cycle. Cell cycle regulatory proteins and protein kinases in signaling pathways affected by growth factors can lead to AR activation in the absence of androgen. While downstream signaling proteins such as cyclins, cyclin-dependent kinases (CDKs), and pRB can modulate AR activity, upstream signaling pathways involving protein kinases such as mitogen-activated protein kinases, protein kinase A, and protein kinase B/Akt can affect post-translational modification of AR to affect not only AR function but also AR stability. Calcium and calmodulin (CaM), essential for proliferation and viability of a number of cells, including prostate cancer cells, play an important role in AR expression, stability, and function. CaM affects AR partly by interacting directly with AR and partly by activating protein kinases such as Akt and DNA-PK that can phosphorylate AR. The ubiquitin/26S proteasome pathway responsible for timely destruction of cell cycle regulatory proteins whose levels impede cell cycle progression also induces AR expression by activating NF-kappaB, and promotes AR activity by participating in the assembly of an AR transcription complex. Maspin, a serine protease inhibitor that is known mostly for its role as a tumor suppressor can also regulate AR intracellular localization and function by competing with AR for binding to the chaperone protein Hsp90 and co-repressor HDAC1, respectively. This perspective reviews the experimental evidence implicating these diverse cellular processes in AR expression, stability, and/or function, and presents a rationale for disrupting these cellular processes as a viable option for the treatment of both the hormone-sensitive and the hormone-insensitive prostate cancer.
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PMID:Regulatory processes affecting androgen receptor expression, stability, and function: potential targets to treat hormone-refractory prostate cancer. 1661 63

Ime2p is a meiosis-specific protein kinase in Saccharomyces cerevisiae that controls multiple steps in meiosis. Although Ime2p is functionally related to the Cdc28p cyclin-dependent kinase (CDK), no cyclin binding partners that regulate its activities have been identified. The sequence of the Ime2p catalytic domain is similar to CDKs and mitogen-activated protein kinases (MAPKs). Ime2p is activated by phosphorylation of its activation loop in a Cak1p-dependent fashion and is subsequently phosphorylated on multiple residues as cells progress through meiosis. In this study, we show that Ime2p purified from meiotic cells is phosphorylated on Thr(242) and Tyr(244) in its activation loop and on Ser(520) and Ser(625) in its C terminus. Ime2p autophosphorylates on threonine in its activation loop in vitro consistent with autophosphorylation of Thr(242) playing a role in its activation. Moreover, autophosphorylation in cis is required for Ime2p to become hyperphosphorylated. Phosphorylation of the C-terminal serines is not essential to sporulation. However, Ime2p C-terminal phosphorylation site mutants genetically interact with components of the FEAR network that controls exit from meiosis I. These data suggest that Ime2p plays a role in controlling the exit from meiosis I and demonstrate that a phospho-modification pathway regulates Ime2p during the different phases of meiotic development.
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PMID:Phosphorylation of Ime2 regulates meiotic progression in Saccharomyces cerevisiae. 1668 73

This study examined the effect of dopamine on DNA synthesis and its related signal cascades in mouse embryonic stem (ES) cells. Dopamine inhibited DNA synthesis in both a dose- and time-dependent manner. Dopamine, SKF 38393 (D1 receptor agonist), and quinpirole (D2 receptor agonist) decreased the level of [(3)H]-thymidine incorporation. The level of cyclic adenosine 3, 5-monophosphate (cAMP) was increased by SKF 38393 but not by quinpirole. The protein kinase C (PKC) protein was translocated from the cytosolic fraction to the membrane compartment by dopamine. Dopamine also increased [Ca(2+)](i), which was blocked by EGTA (an extracellular Ca(2+) chelator), BAPTA-AM (an intracellular Ca(2+) chelator), nifedipine (a L-type Ca(2+) channel blocker), SQ 22536 [an adenylyl cyclase (AC) inhibitor] and neomycin [a phospholipase C (PLC) inhibitor]. Dopamine, SKF 38393, and quinpirole increased the level of p44/42 mitogen-activated protein kinases (MAPKs), p38 MAPK, and stress-activated protein kinase/Jun-N-terminal kinase (SAPK/JNK) phosphorylation. Dopamine also increased level of H(2)O(2) formation and activated the transcription factor family NF-kappaB. Moreover, SKF 38393, quinpirole, and dopamine inhibited cell cycle regulatory proteins, which is consistent with the change in the level of [(3)H]-thymidine incorporation observed. The dopamine-induced decrease in cyclin E, cyclin-dependent protein kinase-2 (CDK-2), and cyclin D1, CDK-4 were blocked by pertussis toxin (G protein inhibitor), SQ 22536, neomycin, bisindolylmaleimide I (PKC inhibitor), SB 203580 (p38 MAPK inhibitor), PD 98059 (p44/42 inhibitor), and SP 600125 (SAPK/JNK inhibitor). In conclusion, dopamine inhibits DNA synthesis in mouse ES cells via the cAMP, Ca(2+)/PKC, MAPKs, and NF-kappaB signaling pathways.
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PMID:Dopamine regulates cell cycle regulatory proteins via cAMP, Ca(2+)/PKC, MAPKs, and NF-kappaB in mouse embryonic stem cells. 1668 61

UVB radiation-induced DNA damage in skin activates cellular pathways involved in DNA repair, cell cycle regulation, and apoptosis, important events that prevent conversion of damaged skin cells into cancer. We reported recently the efficacy of silibinin against photocarcinogenesis along with altered molecular events in tumors (Cancer Research, 64:6349-56, 2004). The molecular and biological events modulated by silibinin in chronically UVB-irradiated skin leading to cancer prevention, however, are not known. Herein, we describe effect of silibinin on skin 15 and 25 weeks after UVB exposure and compared them with molecular alterations in skin tumors. UVB decreased E2F1 but increased E2F2 and E2F3 protein levels in skin, and these were reversed by silibinin treatment. Silibinin-induced E2F1 was accompanied by an inhibition of apoptosis and decreases in p53 and cyclin-dependent kinase inhibitors. Silibinin-caused decrease in E2F2 and E2F3 was accompanied by reduced levels of cyclin-dependent kinases, cyclins, CDC25C, and mitogen-activated protein kinases and Akt signaling and inhibition of cell proliferation. In tumorigenesis protocols, topical or dietary silibinin significantly inhibited tumor appearance and growth. As opposed to UVB-exposed skin, UVB-induced tumors showed elevated levels of E2F1, but these were reduced in silibinin-treated tumors without any effect on E2F2 and E2F3. Contrary to the inhibition of apoptosis and p53 expression in UVB-exposed skin cells, silibinin increased these variables in tumors. These differential effects of silibinin on E2F1 versus E2F2 and E2F3 and their associated molecular alterations and biological effects in chronic UVB-exposed skin suggest their role in silibinin interference with photocarcinogenesis.
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PMID:Differential effect of silibinin on E2F transcription factors and associated biological events in chronically UVB-exposed skin versus tumors in SKH-1 hairless mice. 1692 34

The thyroid hormone (TH), 3,5,3'-triiodothyronine (T(3)), is an important regulator of diverse cellular processes including cell proliferation, differentiation, and apoptosis, with increasing evidence that the modulation of the phosphoproteome is an important factor in the TH-mediated response. However, little is understood regarding the mechanisms whereby phosphorylation may contribute to T(3)-mediated cellular outcomes during development. The cyclin-dependent kinases (Cdks) and mitogen-activated protein kinases (MAPK/ERK) have been implicated in TH signaling in mammalian cells. In this study, we have investigated, in frogs, the possible role that these kinases may have in the promotion of tail regression during tadpole metamorphosis, an important postembryonic process that is completely TH-dependent. Cdk2 steady state levels and activity increase in the tail concurrent with progression through the growth phase of metamorphosis, followed by a precipitous decrease coinciding with tail regression. Cyclin-A-associated kinase activity also follows a similar trend except that its associated kinase activity is maintained longer before a decrease in activity. Protein steady state levels of ERK1 and ERK2 remain relatively constant, and their kinase activities do not decrease until much later during tail regression. Tail tips cultured in serum-free medium in the presence of T(3) undergo regression, which is accelerated by coincubation with a specific Cdk2 inhibitor. Coincubation with PD098059, a MAPK inhibitor, has no effect. Thus, T(3)-dependent tail regression does not require MAPKs, but a decrease in Cdk2 activity promotes tail regression.
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PMID:Decreased cyclin-dependent kinase activity promotes thyroid hormone-dependent tail regression in Rana catesbeiana. 1722 71

Human and animal papillomavirus DNA replicates as multicopy nuclear plasmids. Replication requires two viral proteins, the origin-recognition protein E2 and the replicative DNA helicase E1. Using genetic, biochemical, and immunofluorescence assays, we demonstrated that efficient nuclear import of the human papillomavirus (HPV) type 11 E1 protein depends on a codominant bipartite nuclear localization sequence (NLS) and on phosphorylation of the serine residues S89 and S93 by the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase, and c-Jun N-terminal protein kinase. The NLS and the MAPK substrates are located within a 50-amino-acid-long peptide near the amino terminus, previously designated the localization regulatory region (LRR). The downstream NLS overlaps the cyclin-binding motif RRL, which is necessary for phosphorylation by the cyclin-dependent kinases to inactivate a dominant nuclear export sequence, also in the LRR. Alanine mutations of the MAPK substrates significantly impaired nuclear import, whereas phospho-mimetic mutations partially restored nuclear import. We further identified two MAPK docking motifs near the C terminus of E1 that are conserved among E1 proteins of many HPVs and bovine papillomavirus type 1. Mutations of these MAPK docking motifs or addition of specific MAPK inhibitors significantly reduced nuclear import. Interestingly, a fraction of the NLS-minus E1 protein was cotransported with the E2 protein into the nucleus and supported transient viral DNA replication. In contrast, E1 proteins mutated in the MAPK docking motifs were completely inactive in transient replication, an indication that additional properties were adversely affected by those changes.
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PMID:Mitogen-activated protein kinases activate the nuclear localization sequence of human papillomavirus type 11 E1 DNA helicase to promote efficient nuclear import. 1734 81

Progesterone receptors (PRs) mediate proliferation during breast development and contribute to breast cancer progression, in part by synergizing with peptide growth factors. We have previously identified PR Ser294 as a key site for direct regulation of PR location, activity, and turnover in response to phosphorylation events. Herein, we sought to better understand how hormonal cross talk alters PR function. We demonstrate that progestins (R5020 and RU486) induce rapid (15 min) sumoylation of PR Lys388; sumoylation represses PR transcriptional activity on selected progesterone response element-driven and endogenous promoters and retards ligand-induced PR down-regulation. Consistent with this finding, we show that stabilized but weakly active phospho-mutant S294A PRs are heavily sumoylated. Conversely, desumoylated PR, created by mutation of PR Lys388 (K388R) or by overexpression of sentrin (SUMO)-specific protease desumoylating enzymes, are hypersensitive to low progestin concentrations. Combination of K388R and S294A mutations (KRSA double-mutant PR) rescues both transcription and turnover of impaired phospho-mutant (S294A) receptors. Notably, phosphorylation events antagonize PR-B but not PR-A sumoylation. Treatment of cells with epidermal growth factor or transient expression of activated mitogen-activated protein/ERK kinase kinase or cyclin-dependent protein kinase 2 induces PR-B Ser294 phosphorylation and blocks PR-B sumoylation, thereby derepressing receptor activity; PR-A is resistant to these events. Modulation of reversible PR sumoylation in response to diverse hormonal signals provides a mechanism for rapid isoform-specific changes in hormone responsiveness. In the context of elevated protein kinase activities, such as during mammary gland development or breast cancer progression, phosphorylated PR-B may be undersumoylated, transcriptionally hyperactive, and unstable/undetectable.
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PMID:Phosphorylation-dependent antagonism of sumoylation derepresses progesterone receptor action in breast cancer cells. 1771 77

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, with no effective treatment for most individuals who succumb to this neoplasm. We report that treatment of primary HCC cells with the mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase 1/2 inhibitor AZD6244 (ARRY-142886) plus doxorubicin led to synergistic growth inhibition and apoptosis. In vivo administration of AZD6244, doxorubicin, or the combination of AZD6244 and doxorubicin in mice bearing 5-1318 HCC xenografts resulted in approximately 52% +/- 15%, 12% +/- 9%, and 76% +/- 7% growth inhibition, respectively. AZD6244-inhibited tumor growth was associated with increased apoptosis, inactivation of ERK1/2, inhibition of cell proliferation, and down-regulation of cell cycle regulators, including cyclin D1, cdc-2, cyclin-dependent kinases 2 and 4, cyclin B1, and c-Myc. The AZD6244-doxorubicin combined protocol not only promoted apoptosis but also induced a synergistic effect not seen in single-agent-treated tumors, including increased expression of the p130 RB tumor suppressor gene. Our study provides a strong rationale for clinical investigation of combination therapy with the mitogen-activated protein/ERK kinase 1/2 inhibitor AZD6244 and doxorubicin in patients with HCC.
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PMID:AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma. 1787 44


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