scholarly journals SRSF2 regulation of MDM2 reveals splicing as a therapeutic vulnerability of the p53 pathway

2019 ◽  
Author(s):  
Daniel F. Comiskey ◽  
Matías Montes ◽  
Safiya Khurshid ◽  
Ravi K. Singh ◽  
Dawn S. Chandler
Keyword(s):  
Alternative Splicing ◽  
Stress Condition ◽  
Genotoxic Stress ◽  
Negative Regulator ◽  
Tumor Suppressor P53 ◽  
3T3 Cells ◽  
Splicing Regulator ◽  
Exonic Splicing Enhancers ◽  
Exon 11 ◽  
Nih 3T3

ABSTRACTMDM2 is an oncogene and critical negative regulator of tumor suppressor p53. Genotoxic stress causes alternative splicing of MDM2 transcripts, which leads to alterations in p53 activity and contributes to tumorigenesis. MDM2-ALT1 is one of transcripts predominantly produced in response to genotoxic stress and is comprised of terminal coding exons 3 and 12. Previously, we found that SRSF1 induces MDM2-ALT1 by promoting MDM2 exon 11 skipping. Here we report that splicing regulator SRSF2 antagonizes the regulation of SRSF1 by facilitating the inclusion of exon 11 through binding at two conserved exonic splicing enhancers. Overexpression of SRSF2 reduced the generation of MDM2-ALT1 in genotoxic stress condition, whereas knockdown induces the expression of MDM2-ALT1 in absence of genotoxic stress. Consistently, blocking the exon 11 SRSF2 binding sites using oligonucleotides promotes MDM2-ALT1. The regulation of MDM2 splicing by SRSF2 is also conserved in mouse as mutation of one SRSF2 binding site in Mdm2 exon 11, using CRISPR-Cas9, increases the expression MDM2-ALT1 homolog Mdm2-MS2 and proliferation of NIH 3T3 cells. Taken together, these findings underscore the relevance of MDM2 alternative splicing in cancer and suggest that p53 levels can be modulated by artificially regulating MDM2 splicing.

Both products of the fosB gene, FosB and its short form, FosB/SF, are transcriptional activators in fibroblasts

1991 ◽  
Vol 11 (11) ◽  
pp. 5470-5478
Author(s):  
P Dobrazanski ◽  
T Noguchi ◽  
K Kovary ◽  
C A Rizzo ◽  
P S Lazo ◽  
...  
Keyword(s):  
Amino Acids ◽  
Cell Cycle Progression ◽  
Short Form ◽  
Constitutive Expression ◽  
Inhibitory Effect ◽  
Negative Regulator ◽  
3T3 Cells ◽  
C Terminus ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

We demonstrate that a member of the fos family, the fosB gene, gives rise to two transcripts by alternative splicing of exon 4, generating two proteins, FosB of 338 amino acids and a short form, FosB/SF, which contains the DNA binding and dimerization domains but not the 101 amino acids of the C terminus. FosB/SF activates an AP-1-chloramphenicol acetyltransferase construct in NIH 3T3 cells, as determined by transient and stable transfections, although more weakly than does FosB. In contrast to FosB, FosB/SF has lost its ability to repress the dyad symmetry element of the c-fos gene. FosB/SF when expressed in excess to FosB can downmodulate the activity of FosB. Constitutive expression of high levels of FosB/SF in NIH 3T3 cells has no significant inhibitory effect in the induction of cell proliferation or cell cycle progression, indicating that FosB/SF is not a negative regulator of cell growth. This conclusion is further confirmed by the observation that the majority of the Jun molecules are complexed with FosB/SF in the FosB/SF-overexpressing cells.

scholarly journals Downregulation of DUSP6, a negative regulator of oncogenic ERK signaling, by ACA‐28 induces apoptosis in NIH/3T3 cells overexpressing HER2/ErbB2

2020 ◽  
Author(s):  
Yuki Kanda ◽  
Ayami Mizuno ◽  
Teruaki Takasaki ◽  
Ryosuke Satoh ◽  
Kanako Hagihara ◽  
...  
Keyword(s):  
Negative Regulator ◽  
Erk Signaling ◽  
3T3 Cells ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

scholarly journals Both products of the fosB gene, FosB and its short form, FosB/SF, are transcriptional activators in fibroblasts.

1991 ◽  
Vol 11 (11) ◽  
pp. 5470-5478 ◽  
Author(s):  
P Dobrazanski ◽  
T Noguchi ◽  
K Kovary ◽  
C A Rizzo ◽  
P S Lazo ◽  
...  
Keyword(s):  
Amino Acids ◽  
Cell Cycle Progression ◽  
Short Form ◽  
Constitutive Expression ◽  
Inhibitory Effect ◽  
Negative Regulator ◽  
3T3 Cells ◽  
C Terminus ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

We demonstrate that a member of the fos family, the fosB gene, gives rise to two transcripts by alternative splicing of exon 4, generating two proteins, FosB of 338 amino acids and a short form, FosB/SF, which contains the DNA binding and dimerization domains but not the 101 amino acids of the C terminus. FosB/SF activates an AP-1-chloramphenicol acetyltransferase construct in NIH 3T3 cells, as determined by transient and stable transfections, although more weakly than does FosB. In contrast to FosB, FosB/SF has lost its ability to repress the dyad symmetry element of the c-fos gene. FosB/SF when expressed in excess to FosB can downmodulate the activity of FosB. Constitutive expression of high levels of FosB/SF in NIH 3T3 cells has no significant inhibitory effect in the induction of cell proliferation or cell cycle progression, indicating that FosB/SF is not a negative regulator of cell growth. This conclusion is further confirmed by the observation that the majority of the Jun molecules are complexed with FosB/SF in the FosB/SF-overexpressing cells.

scholarly journals Heat Shock Protein Hsp72 Is a Negative Regulator of Apoptosis Signal-Regulating Kinase 1

2002 ◽  
Vol 22 (22) ◽  
pp. 7721-7730 ◽  
Author(s):  
Hee-Sae Park ◽  
Ssang-Goo Cho ◽  
Chang Kyun Kim ◽  
Hyun Sub Hwang ◽  
Kyung Tae Noh ◽  
...  
Keyword(s):  
Heat Shock ◽  
Protein Kinase ◽  
Heat Shock Protein ◽  
Mapk Signaling ◽  
Negative Regulator ◽  
Physical Interaction ◽  
3T3 Cells ◽  
Mild Heat ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

ABSTRACT Heat shock protein 72 (Hsp72) is thought to protect cells against cellular stress. The protective role of Hsp72 was investigated by determining the effect of this protein on the stress-activated protein kinase signaling pathways. Prior exposure of NIH 3T3 cells to mild heat shock (43°C for 20 min) resulted in inhibition of H2O2-induced activation of apoptosis signal-regulating kinase 1 (ASK1). Overexpression of Hsp72 also inhibited H2O2-induced activation of ASK1 as well as that of downstream kinases in the p38 mitogen-activated protein kinase (MAPK) signaling cascade. Recombinant Hsp72 bound directly to ASK1 and inhibited ASK1 activity in vitro. Furthermore, coimmunoprecipitation analysis revealed a physical interaction between endogenous Hsp72 and ASK1 in NIH 3T3 cells exposed to mild heat shock. Hsp72 blocked both the homo-oligomerization of ASK1 and ASK1-dependent apoptosis. Hsp72 antisense oligonucleotides prevented the inhibitory effects of mild heat shock on H2O2-induced ASK1 activation and apoptosis. These observations suggest that Hsp72 functions as an endogenous inhibitor of ASK1.

Differential effect of pp120 on insulin endocytosis by two variant insulin receptor isoforms

1997 ◽  
Vol 273 (4) ◽  
pp. E801-E808 ◽  
Author(s):  
Sergio Li Calzi ◽  
Curtis V. Choice ◽  
Sonia M. Najjar
Keyword(s):  
Insulin Receptor ◽  
3T3 Cells ◽  
Insulin Receptor Tyrosine Kinase ◽  
Α Subunit ◽  
3T3 Fibroblasts ◽  
Receptor Isoforms ◽  
Insulin Receptor Isoforms ◽  
Exon 11 ◽  
Isoform B ◽  
Nih 3T3

The insulin receptor is expressed as two variably spliced isoforms that differ by the absence (isoform A) or presence (isoform B) of a 12-amino acid sequence encoded by exon 11 at the carboxy terminus of the α-subunit. Coexpression of the A isoform and pp120, a substrate of the insulin receptor tyrosine kinase, in NIH 3T3 fibroblasts increased receptor A-mediated insulin endocytosis and degradation by two- to threefold compared with cells expressing receptors alone. Because B is the predominant isoform in the liver and binds insulin with lower affinity than A, we have examined the effect of pp120 on receptor B-mediated endocytosis. In contrast to isoform A, the effect of pp120 on isoform B-mediated insulin internalization and degradation in stably transfected NIH 3T3 cells was minimal.

scholarly journals Overexpression of protein kinase C-delta and -epsilon in NIH 3T3 cells induces opposite effects on growth, morphology, anchorage dependence, and tumorigenicity.

1993 ◽  
Vol 268 (9) ◽  
pp. 6090-6096 ◽  
Author(s):  
H. Mischak ◽  
J.A. Goodnight ◽  
W. Kolch ◽  
G. Martiny-Baron ◽  
C. Schaechtle ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
3T3 Cells ◽  
Growth Morphology ◽  
Protein Kinase C Delta ◽  
Kinase C ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

U2AF - Hypoxia-induced fas alternative splicing regulator

2021 ◽  
Vol 399 (1) ◽  
pp. 112444
Author(s):  
Laurynas Vilys ◽  
Inga Peciuliene ◽  
Egle Jakubauskiene ◽  
Ruta Zinkeviciute ◽  
Yuichi Makino ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Splicing Regulator

Metabolism of n-6 fatty acids by NIH-3T3 cells transfected with the ras oncogene

1994 ◽  
Vol 139 (1) ◽  
pp. 71-81 ◽  
Author(s):  
R. J. de Antueno ◽  
R. C. Cantrill ◽  
Y-S. Huang ◽  
G. W. Ells ◽  
M. Elliot ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Ras Oncogene ◽  
3T3 Cells ◽  
Nih 3T3 ◽  
Nih 3T3 Cells
Sign in / Sign up

Export Citation Format

Share Document