Transcriptional repression of the RET proto-oncogene by a mitogen activated protein kinase-dependent signalling pathway

Heat stress has long been recognised as a cause of subfertility in farm animals. The objectives of the present study were to elucidate the effect of heat stress on sperm function and involvement of the mitogen-activated protein kinase (MAPK) 14 signalling pathway. Spermatozoa incubated for 4 h at a physiological temperature (38.5°C) exhibited significantly (P < 0.05) reduced motility, plasma membrane integrity and mitochondrial potential compared with non-incubated spermatozoa; the reductions in these parameters were more severe following incubation at a hyperthermic (41°C) temperature (P < 0.01). Percentages of fertilisation and embryo development were highly affected in spermatozoa incubated at 41°C compared with non-incubated spermatozoa (P < 0.01). Similarly, embryo quality was adversely affected by sperm incubation at 41°C, as indicated by a higher apoptotic cell ratio in Day 7 blastocysts compared with that in the non-incubated control group (14.6% vs 6.7%, respectively; P < 0.01). Using SB203580 (10 µg mL–1), a specific inhibitor of the p38 MAPK pathway, during sperm hyperthermia reduced MAPK14 activation (24.9% vs 35.6%), increased sperm motility (45.8% vs 26.5%) and reduced DNA fragmentation (16.9% vs 23.4%) compared with the untreated control group, but did not improve subsequent fertilisation and embryo development. In conclusion, heat stress significantly affects the potential of spermatozoa to penetrate oocytes, as well as subsequent embryo development and quality. Notably, the data show that the MAPK14 signalling pathway is largely involved in heat-induced sperm damage. However, further research is needed to elucidate other signalling pathways possibly involved in heat-induced sperm damage.

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Mitogen-activated protein kinase mediates erythropoietin-induced phosphorylation of the TAL1/SCL transcription factor in murine proerythroblasts

Biochemical Journal ◽

10.1042/bj3430615 ◽

1999 ◽

Vol 343 (3) ◽

pp. 615-620 ◽

Cited By ~ 7

Author(s):

Tong TANG ◽

K. S. Srinivasa PRASAD ◽

Mark J. KOURY ◽

Stephen J. BRANDT

Keyword(s):

Transcription Factor ◽

Protein Kinase ◽

Kinase Inhibitor ◽

Erythroid Differentiation ◽

Signalling Pathway ◽

Mitogen Activated Protein Kinase ◽

Friend Virus ◽

Phosphatidylinositol 3 Kinase ◽

Mitogen Activated Protein ◽

Protein Kinase Kinase

Ectopic expression of the basic helix-loop-helix transcription factor TAL1 (or SCL) is the most frequent gain-of-function mutation in T-cell acute lymphoblastic leukaemia. Gene-knockout studies in mice have demonstrated that TAL1 is required for embryonic and adult haematopoiesis, and considerable evidence suggests it also has important functions in terminal erythroid differentiation. We reported previously that TAL1 phosphorylation is stimulated by erythropoietin in splenic proerythroblasts isolated from mice infected with the anaemia-inducing strain of Friend virus and show here the signalling pathway responsible. Erythropoietin was found to stimulate nuclear mitogen-activated protein kinase activity in addition to TAL1 protein phosphorylation, both of which were quantitatively inhibited by the mitogen-activated protein kinase kinase inhibitor PD 098059 and the phosphatidylinositol 3-kinase inhibitor wortmannin. Tryptic phosphopeptide analysis of radiolabelled TAL1 immunoprecipitated from nuclear extracts of Friend virus-induced proerythroblasts revealed that phosphorylation of Ser122, shown previously to be a substrate for the mitogen-activated protein kinase ERK1 (extracellular signal-regulated protein kinase) in vitro, was specifically, although not exclusively, increased by erythropoietin and inhibited by wortmannin and PD 098059. These results are consistent with an erythropoietin-stimulated signalling pathway in which there is direct activation of a mitogen-activated protein kinase kinase by phosphatidylinositol 3-kinase and identify TAL1 as one of its nuclear targets. These data suggest, in addition, a specific mechanism by which the principal regulator of erythroid differentiation could enhance TAL1 function, in addition to increasing its expression.

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Isoquercitrin inhibits the progression of pancreatic cancer in vivo and in vitro by regulating opioid receptors and the mitogen-activated protein kinase signalling pathway

Oncology Reports ◽

10.3892/or.2014.3626 ◽

2014 ◽

Vol 33 (2) ◽

pp. 840-848 ◽

Cited By ~ 35

Author(s):

QUAN CHEN ◽

PING LI ◽

YONG XU ◽

YANG LI ◽

...

Keyword(s):

Pancreatic Cancer ◽

Protein Kinase ◽

Opioid Receptors ◽

Signalling Pathway ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Protein Kinase Signalling

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Repression of Ribosome and tRNA Synthesis in Secretion-Defective Cells Is Signaled by a Novel Branch of the Cell Integrity Pathway

Molecular and Cellular Biology ◽

10.1128/mcb.20.11.3843-3851.2000 ◽

2000 ◽

Vol 20 (11) ◽

pp. 3843-3851 ◽

Cited By ~ 95

Author(s):

Yun Li ◽

Robyn D. Moir ◽

Indra K. Sethy-Coraci ◽

Jonathan R. Warner ◽

Ian M. Willis

Keyword(s):

Protein Kinase ◽

Transcriptional Repression ◽

Secretory Pathway ◽

Turgor Pressure ◽

Mitogen Activated Protein Kinase ◽

Trna Genes ◽

Cell Integrity ◽

Effector Pathway ◽

Mitogen Activated Protein ◽

Kinase Cascade

ABSTRACT The transcription of ribosomal DNA, ribosomal protein (RP) genes, and 5S and tRNA genes by RNA polymerases (Pols) I, II, and III, respectively, is rapidly and coordinately repressed upon interruption of the secretory pathway in Saccharomyces cerevisiae. We find that repression of ribosome and tRNA synthesis in secretion-defective cells involves activation of the cell integrity pathway. Transcriptional repression requires the upstream components of this pathway, including the Wsc family of putative plasma membrane sensors and protein kinase C (PKC), but not the downstream Bck1–Mkk1/2–Slt2 mitogen-activated protein kinase cascade. These findings reveal a novel PKC effector pathway that controls more than 85% of nuclear transcription. It is proposed that the coordination of ribosome and tRNA synthesis with cell growth may be achieved, in part, by monitoring the turgor pressure of the cell.

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Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway.

Molecular and Cellular Biology ◽

10.1128/mcb.16.10.5839 ◽

1996 ◽

Vol 16 (10) ◽

pp. 5839-5845 ◽

Cited By ~ 187

Author(s):

T W Schulte ◽

M V Blagosklonny ◽

L Romanova ◽

J F Mushinski ◽

B P Monia ◽

...

Keyword(s):

Protein Kinase ◽

Phorbol Esters ◽

Signalling Pathway ◽

Mitogen Activated Protein Kinase ◽

Mapk Signalling Pathway ◽

Mapk Signalling ◽

Mitogen Activated Protein ◽

And Function ◽

Nih 3T3 ◽

Benzoquinone Ansamycin

The serine/threonine kinase Raf-1 functions downstream of Rats in a signal transduction cascade which transmits mitogenic stimuli from the plasma membrane to the nucleus. Raf-1 integrates signals coming from extracellular factors and, in turn, activates its substrate, MEK kinase. MEK activates mitogen-activated protein kinase (MAPK), which phosphorylates other kinases as well as transcription factors. Raf-1 exists in a complex with HSP90 and other proteins. The benzoquinone ansamycin geldanamycin (GA) binds to HSP90 and disrupts the Raf-1-HSP90 multimolecular complex, leading to destabilization of Raf-1. In this study, we examined whether Raf-1 destabilization is sufficient to block the Raf-1-MEK-MAPK signalling pathway and whether GA specifically inactivates the Raf-1 component of this pathway. Using the model system of NIH 3T3 cells stimulated with phorbol 12-myristate 13-acetate (PMA), we show that GA does not affect the ability of protein kinase C alpha to be activated by phorbol esters, but it does block activation of MEK and MAPK. Further, GA does not decrease the activity of constitutively active MEK in transiently transfected cells. Finally, disruption of the Raf-1-MEK-MAPK signalling pathway by GA prevents both the PMA-induced proliferative response and PMA-induced activation of a MAPK-sensitive nuclear transcription factor. Thus, we demonstrate that interaction between HSP90 and Raf-1 is a sine qua non for Raf stability and function as a signal transducer and that the effects observed cannot be attributed to a general impairment of protein kinase function.

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The regulation of ATF3 gene expression by mitogen-activated protein kinases

Biochemical Journal ◽

10.1042/bj20061081 ◽

2006 ◽

Vol 401 (2) ◽

pp. 559-567 ◽

Cited By ~ 107

Author(s):

Dan Lu ◽

Jingchun Chen ◽

Tsonwin Hai

Keyword(s):

Transcription Factor ◽

Protein Kinase ◽

Critical Role ◽

Ectopic Expression ◽

Signalling Pathway ◽

Mitogen Activated Protein Kinase ◽

Wide Range ◽

Mitogen Activated Protein ◽

Stress Signals ◽

P38 Pathway

ATF3 (activating transcription factor 3) gene encodes a member of the ATF/CREB (cAMP-response-element-binding protein) family of transcription factors. Its expression is induced by a wide range of signals, including stress signals and signals that promote cell proliferation and motility. Thus the ATF3 gene can be characterized as an ‘adaptive response’ gene for the cells to cope with extra- and/or intra-cellular changes. In the present study, we demonstrate that the p38 signalling pathway is involved in the induction of ATF3 by stress signals. Ectopic expression of CA (constitutively active) MKK6 [MAPK (mitogen-activated protein kinase) kinase 6], a kinase upstream of p38, indicated that activation of the p38 pathway is sufficient to induce the expression of the ATF3 gene. Inhibition of the pathway indicated that the p38 pathway is necessary for various signals to induce ATF3, including anisomycin, IL-1β (interleukin 1β), TNFα (tumour necrosis factor α) and H2O2. Analysis of the endogenous ATF3 gene indicates that the regulation is at least in part at the transcription level. Specifically, CREB, a transcription factor known to be phosphorylated by p38, plays a role in this induction. Interestingly, the ERK (extracellular-signal-regulated kinase) and JNK (c-Jun N-terminal kinase)/SAPK (stress-activated protein kinase) signalling pathways are neither necessary nor sufficient to induce ATF3 in the anisomycin stress paradigm. Furthermore, analysis of caspase 3 activation indicated that knocking down ATF3 reduced the ability of MKK6(CA) to exert its pro-apoptotic effect. Taken together, our results indicate that a major signalling pathway, the p38 pathway, plays a critical role in the induction of ATF3 by stress signals, and that ATF3 is functionally important to mediate the pro-apoptotic effects of p38.

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