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

Elucidation of mechanisms regulating cell cycle progression is of fundamental importance for cell and cancer biology. Although several genes and signaling pathways are implicated in G1-S regulation, less is known regarding the mechanisms controlling cell cycle progression through G2 and M phases. We report that extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinases, is activated at G2-M and required for timely mitotic entry. Stimulation of ERK5 activated nuclear factor kappaB (NFkappaB) through ribosomal S6 kinase 2 (RSK2)-mediated phosphorylation and degradation of IkappaB. Furthermore, selective inhibition of NFkappaB at G2-M phases substantially delayed mitotic entry and inhibited transcription of G2-M-specific genes, including cyclin B1, cyclin B2, Plk-1, and cdc25B. Moreover, inhibition of NFkappaB at G2-M diminished mitosis induced by constitutive activation of ERK5, providing a direct link between ERK5, NFkappaB, and regulation of G2-M progression. We conclude that a novel ERK5-NFkappaB signaling pathway plays a key role in regulation of the G2-M progression.
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PMID:Regulation of the G2-M cell cycle progression by the ERK5-NFkappaB signaling pathway. 1745 29