Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RASSF1A is a tumor suppressor gene that is epigenetically silenced in a wide variety of sporadic human malignancies. Expression of alternative RASSF1 isoforms cannot substitute for RASSF1A-promoted cell-cycle arrest and apoptosis. Apoptosis can be driven by either activating Bax or by activation of MST kinases. The Raf1 proto-oncogene binds to MST2, preventing its activation and proapoptotic signaling. Here we show that key steps in RASSF1A-induced apoptosis are the disruption of the inhibitory Raf1-MST2 complex by RASSF1A and the concomitant enhancement of MST2 interaction with its substrate, LATS1. Subsequently, RASSF1A-activated LATS1 phosphorylates and releases the transcriptional regulator YAP1, allowing YAP1 to translocate to the nucleus and associate with p73, resulting in transcription of the proapoptotic target gene puma. Our results describe an MST2-dependent effector pathway for RASSF1A proapoptotic signaling and indicate that silencing of RASSF1A in tumors removes a proapoptotic signal emanating from p73.
Mol Cell 2007 Sep 21
PMID:RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein. 1788 59

The telomeric poly(ADP-ribose) polymerase (PARP), tankyrase 1, modulates the impact of telomerase inhibition on human cancer cells. Thus, overexpression of tankyrase 1 in telomerase-positive cancer cells confers resistance to telomerase inhibitors, such as MST-312, whereas pharmacological inhibition of tankyrase 1 enhances telomere shortening by MST-312. These facts indicate that tankyrase 1 could be a target for telomere-directed molecular cancer therapy. Here, the authors describe a convenient method to monitor the telomeric function of tankyrase 1. This protocol takes much less time than the telomere Southern blot analysis and can be utilized as a rapid screening system for tankyrase 1 inhibitors that are effective in intact cells. For direct monitoring of tankyrase 1 PARP activity, a protocol for the in vitro enzyme assay is also described.
Methods Mol Biol 2007
PMID:Evaluation of tankyrase inhibition in whole cells. 1836 22

The MST family of protein kinases plays a critical role in the regulation of cell death in diverse organisms including mammals. The intracellular signaling pathways that regulate MST-driven cell death in mammalian cells are the subject of intense investigation. Stress stimuli including oxidative stress and DNA damaging agents trigger the activity of MST in cells. Although the mechanisms by which oxidative stress and DNA damage trigger MST activation remain to be identified, MST activity can be regulated by caspase-induced cleavage as well as interactions with other proteins in cells. Once activated upon oxidative stress, MST induces cell death via phosphorylation and activation of the transcription factor FOXO3 or the histone protein H2B. This review focuses on the currently known upstream activating mechanisms for MST, and explores the downstream signaling pathways that mediate MST's principal function in cell death. Elucidation of MST functions and their regulatory mechanisms in cell death have important implications for our understanding of cellular homeostasis as well as the pathogenesis of diverse diseases.
Curr Mol Med 2008 Jun
PMID:Demystifying MST family kinases in cell death. 1853 38

SHH, IHH, and DHH are lipid-modified secreted proteins binding to Patched receptors, and CDON, BOC or GAS1 co-receptors. In the absence of Hedgehog signaling, GLI1 is transcriptionally repressed, GLI2 is phosphorylated by GSK3 and CK1 for the FBXW11 (betaTRCP2)-mediated degradation, and GLI3 is processed to a cleaved repressor. In the presence of Hedgehog signaling, Smoothened is relieved from Patched-mediated suppression due to the Hedgehog-dependent internalization of Patched, which leads to MAP3K10 (MST) activation and SUFU inactivation for the stabilization and nuclear accumulation of GLI family members. GLI activators then upregulate CCND1, CCND2 for cell cycle acceleration, FOXA2, FOXC2, FOXE1, FOXF1, FOXL1, FOXP3, POU3F1, RUNX2, SOX13, TBX2 for cell fate determination, JAG2, INHBC, and INHBE for stem cell signaling regulation. Hedgehog signals also upregulate SFRP1 in mesenchymal cells for WNT signaling regulation. Epithelial-to-mesenchymal transition (EMT) during embryogenesis, adult tissue homeostasis and carcinogenesis is characterized by class switch from E-cadherin to N-cadherin. SNAI1 (Snail), SNAI2 (Slug), SNAI3, ZEB1, ZEB2 (SIP1), KLF8, TWIST1, and TWIST2 are EMT regulators repressing CDH1 gene encoding E-cadherin. Hedgehog signals induce JAG2 upregulation for Notch-CSL-mediated SNAI1 upregulation, and also induce TGFbeta1 secretion for ZEB1 and ZEB2 upregulation via TGFbeta receptor and NF-kappaB. TGFbeta-mediated downregulation of miR-141, miR-200a, miR-200b, miR-200c, miR-205, and miR-429 results in upregulation of ZEB1 and ZEB2 proteins. Hedgehog signaling activation indirectly leads to EMT through FGF, Notch, TGFbeta signaling cascades, and miRNA regulatory networks. miRNAs targeted to stem cell signaling components or EMT regulators are potent drug targets; however, off-target effects should be strictly controlled before clinical application of synthetic miRNA. Peptide mimetic and RNA aptamer could also be utilized as Hedgehog signaling inhibitors or EMT suppressors.
Int J Mol Med 2008 Sep
PMID:Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). 1869 84

Activator protein 1 (JUN) transcription factors (JUN and FOS) play critical roles in a wide variety of signaling processes including those in the protein kinase C (PRKCC) pathway, a pathway that is instrumental in the expression of the steroidogenic acute regulatory (STAR) protein. In the present study, we determined the functional involvement of one of the key JUN family members, JUN, in the regulation of PRKCC-dependent STAR expression and steroidogenesis. MA-10 mouse Leydig tumor cells treated with an activator of PRKCC, phorbol 12-myristate 13-acetate (PMA), demonstrated increases in the expression of the STAR and CYP11A1 proteins and progesterone synthesis, which coincided with the expression and phosphorylation of JUN (P-JUN). PMA was also capable of enhancing the cAMP analog, (Bu)(2)cAMP, which stimulated JUN, STAR, P-STAR and progesterone levels. The induction of Jun mRNA expression and steroid synthesis by PMA requires de novo protein synthesis. Chromatin immunoprecipitation studies revealed the association of P-JUN with the STAR proximal promoter and that PMA specifically enhanced in vivo P-JUN-DNA interaction. Electrophoretic mobility shift assays and reporter gene analyses demonstrated that JUN binds to the JUN motif (-81/-75 bp) in the STAR promoter, and that JUN-DNA-binding activity was highly correlated with the induction of JUN by PRKCC signaling. Overexpression of JUN increased the PMA-mediated transcription of the Star gene, an event markedly decreased by TAM-67, a dominant negative mutant of JUN. Targeted silencing of endogenous JUN, by small interfering RNA, was correlated with the repression of basal- and PMA-mediated STAR expression and progesterone synthesis. These findings describe the mechanisms by which JUN influences PRKCC signaling and provide additional and novel insight into the regulation of the steroidogenic machinery in mouse Leydig cells.
J Mol Endocrinol 2008 Nov
PMID:The role of JUN in the regulation of PRKCC-mediated STAR expression and steroidogenesis in mouse Leydig cells. 1875 54

GnRH neurons must undergo a complex and precise pattern of neuronal migration to appropriately target their projections to the median eminence to trigger gonadotropin secretion and thereby control reproduction. Using NLT GnRH cells as a model of early GnRH neuronal development, we identified the potential importance of Axl and Tyro3, members of the TAM (Tyro3, Axl, and Mer) family of receptor tyrosine kinases in GnRH neuronal cell survival and migration. Silencing studies evaluated the role of Tyro3 and Axl in NLT GnRH neuronal cells and suggest that both play a role in Gas6 stimulation of GnRH neuronal survival and migration. Analysis of mice null for both Axl and Tyro3 showed normal onset of vaginal opening but delayed first estrus and persistently abnormal estrous cyclicity compared with wild-type controls. Analysis of GnRH neuronal numbers and positioning in the adult revealed a total loss of 24% of the neuronal network that was more striking (34%) when considered within specific anatomical compartments, with the largest deficit surrounding the organum vasculosum of the lamina terminalis. Analysis of GnRH neurons during embryogenesis identified a striking loss of immunoreactive cells within the context of the ventral forebrain compartment (36%) and not more rostrally. Studies using caspase 3 cleavage as a marker of apoptosis showed that Axl(-/-), Tyro3(-/-) double-knockout mice had increased cell death in the nose and dorsal forebrain, supporting the underlying mechanism of cell loss. Together these data suggest that Axl and Tyro3 mediate the survival and appropriate targeting of GnRH neurons to the ventral forebrain, thereby contributing to normal reproductive function and cyclicity in the female.
Mol Endocrinol 2008 Nov
PMID:Axl and Tyro3 modulate female reproduction by influencing gonadotropin-releasing hormone neuron survival and migration. 1878 40

Tamoxifen has efficacy as a breast cancer therapy and chemoprevention agent. However, toxicity and resistance to tamoxifen limit its clinical application. There is an urgent need to develop compounds that may be combined with tamoxifen to improve efficacy and overcome toxicity and resistance. We showed previously that the organoselenium compound methylseleninic acid (MSA) increased the growth-inhibitory effect of tamoxifen and reversed tamoxifen resistance in breast cancer cells. In this study, we examined the mechanism for induction of apoptosis by MSA combined with tamoxifen in tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. 4-hydroxytamoxifen (TAM; 10(-7) mol/L) alone resulted in cell cycle arrest but no apoptosis, whereas MSA alone (10 micromol/L) induced apoptosis in tamoxifen-sensitive cells. Combination of MSA with TAM resulted in a synergistic apoptosis in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells compared with either agent alone. MSA and MSA combined with TAM induced apoptosis through the intrinsic, mitochondrial apoptotic pathway. MSA induced a sequential activation of caspase-9 and then caspase-8. These results indicate that the growth inhibition synergy and reversal of tamoxifen resistance by combination of selenium with tamoxifen occurs via a tamoxifen-induced cell cycle arrest, allowing more cells to enter the intrinsic apoptotic pathway elicited by selenium.
Mol Cancer Ther 2008 Sep
PMID:Methylseleninic acid synergizes with tamoxifen to induce caspase-mediated apoptosis in breast cancer cells. 1879 Jul 85

The Myc transcription factor is a potent inducer of proliferation and is required for Wnt/beta-catenin signaling in intestinal epithelium. Since deregulation of the Wnt/beta-catenin pathway is a prerequisite for nonhereditary intestinal tumorigenesis, we asked whether activation of Myc recapitulates the tumorigenic changes that are driven by constitutive Wnt/beta-catenin pathway signaling following adenomatous polyposis coli (APC) inactivation. Using mice in which expression of MycER(TAM), a reversibly switchable form of Myc, is expressed transgenically in intestinal epithelium, we define the acute changes that follow Myc activation as well as subsequent deactivation. Myc activation reversibly recapitulates many, but not all, aspects of APC inactivation, including increased proliferation and apoptosis and loss of goblet cells. However, whereas APC inactivation induces redistribution of Paneth cells, direct Myc activation triggers their rapid attrition. Moreover, direct Myc activation engages the ARF/p53/p21(cip1) tumor suppressor pathway, whereas deregulation of Wnt/beta-catenin signaling does not. These observations illustrate key differences in oncogenic impact in intestinal epithelium of direct Myc activation and indirect Myc activation via the Wnt/beta-catenin pathway. Furthermore, the in situ dedifferentiation of mature goblet cells that Myc induces indicates a novel cross talk between the Wnt/beta-catenin and Notch signaling pathways.
Mol Cell Biol 2009 Oct
PMID:Acute overexpression of Myc in intestinal epithelium recapitulates some but not all the changes elicited by Wnt/beta-catenin pathway activation. 1963 9

In the individual application of adriamycin, mitomycin, vindesine and their combined application with tamoxifen for the pre-treatment of the human cholangiocarcinoma cell line QBC939, QBC939 was determined by MTT assay to investigate the inhibitive effect and its initial mechanism of TAM on cell growth. Growth cycle and apoptosis of each group were determined by flow cytometry. Concentration of ADM in QBC939 was detected by flow cytometry. The levels of their P-glycoprotein were detected by immunohistochemistry. The mRNA and protein levels of apoptotic-associated genes Bcl-2 and Bax were determined by western blot and real-time PCR. The inhibitive rates of adriamycin, mitomycin, vindesine to QBC939 and the apoptosis rates of QBC939 were enhanced after the pre-treatment of tamoxifen. Influence of tamoxifen in their growth cycle was not so obvious except vindesine group because of the increasing cell numbers of G (2)/M phase in which cells may be blocked. The contents of adriamycin in cells rose after the pre-treatment of tamoxifen. Expression level of the multi-drug resistant protein on cell surface was shown as (+). Furthermore, real-time PCR and Western blot analysis revealed an upregulation of Bcl-2 and a downregulation of Bax in QBC939 after the pre-treatment of tamoxifen. Therefore, tamoxifen may have the ability to enhance the relative sensitivity of QBC939 to chemotherapeutics.
Mol Biol Rep 2010 Jul
PMID:The growth-inhibition effect of tamoxifen in the combination chemotherapeutics on the human cholangiocarcinoma cell line QBC939. 1975 72

The IEF-MST continuum solvation model is used to predict the hydration free energies and tautomeric preferences of a set of multifunctional compounds compiled as a blind test for computational solvation methods in the SAMPL2 contest. Computations of hydration free energies was performed using both HF/6-31G(d) and B3LYP/6-31G(d) versions of the IEF-MST model. For tautomeric preferences, the IEF-MST data was combined with the gas phase free energy differences predicted at different levels of theory ranging from MP2/6-31+G(d) to MP2/CBS+[CCSD-MP2/6-31+G(d)] levels. Comparison with the experimental data provided for hydration free energies yields a root-mean square deviation (rmsd) close to 2.3 kcal/mol, which is quite remarkable, especially considering the reduced set of training compounds used in the parametrization of the IEF-MST method. With regard to tautomerism, the lowest error in the prediction of the relative stabilities between tautomers in solution is obtained by combining MP2/CBS+[CCSD-MP2/6-31+G(d)] results with IEF-MST hydration free energies, yielding a rmsd of ca. 3.4 kcal/mol. The results illustrate the delicate balance that must be kept between the intrinsic relative stabilities in the gas phase and the differential hydration preferences in order to obtain an accurate description of the prototropic tautomerism in bioorganic compounds.
J Comput Aided Mol Des 2010 Apr
PMID:Performance of the IEF-MST solvation continuum model in the SAMPL2 blind test prediction of hydration and tautomerization free energies. 2030 Aug 1


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