scholarly journals Activation of Tripartite Motif Containing 63 Expression by Transcription Factor EB and Transcription Factor Binding to Immunoglobulin Heavy Chain Enhancer 3 Is Regulated by Protein Kinase D and Class IIa Histone Deacetylases

2021 ◽  
Vol 11 ◽  
Author(s):  
Cristina Pablo Tortola ◽  
Britta Fielitz ◽  
Yi Li ◽  
Julia Rüdebusch ◽  
Friedrich C. Luft ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Heavy Chain ◽  
Nuclear Export ◽  
Immunoglobulin Heavy Chain ◽  
Inhibitory Effect ◽  
Physical Interaction ◽  
Tripartite Motif ◽  
Transcription Factor Eb ◽  
Class Iia Hdacs

RationaleThe ubiquitin–proteasome system (UPS) is responsible for skeletal muscle atrophy. We showed earlier that the transcription factor EB (TFEB) plays a role by increasing E3 ubiquitin ligase muscle really interesting new gene-finger 1(MuRF1)/tripartite motif-containing 63 (TRIM63) expression. MuRF 1 ubiquitinates structural proteins and mediates their UPS-dependent degradation. We now investigated how TFEB-mediated TRIM63 expression is regulated.ObjectiveBecause protein kinase D1 (PKD1), histone deacetylase 5 (HDAC5), and TFEB belong to respective families with close structural, regulatory, and functional properties, we hypothesized that these families comprise a network regulating TRIM63 expression.Methods and ResultsWe found that TFEB and transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) activate TRIM63 expression. The class IIa HDACs HDAC4, HDAC5, and HDAC7 inhibited this activity. Furthermore, we could map the HDAC5 and TFE3 physical interaction. PKD1, PKD2, and PKD3 reversed the inhibitory effect of all tested class IIa HDACs toward TFEB and TFE3. PKD1 mediated nuclear export of all HDACs and lifted TFEB and TFE3 repression. We also mapped the PKD2 and HDAC5 interaction. We found that the inhibitory effect of PKD1 and PKD2 toward HDAC4, HDAC5, and HDAC7 was mediated by their phosphorylation and 14-3-3 mediated nuclear export.ConclusionTFEB and TFE3 activate TRIM63 expression. Both transcription factors are controlled by HDAC4, HDAC5, HDAC7, and all PKD-family members. We propose that the multilevel PKD/HDAC/TFEB/TFE3 network tightly controls TRIM63 expression.

scholarly journals Evidence for Physical Interaction between the Immunoglobulin Heavy Chain Variable Region and the 3′ Regulatory Region

2007 ◽  
Vol 282 (48) ◽  
pp. 35169-35178 ◽  
Author(s):  
Zhongliang Ju ◽  
Sabrina A. Volpi ◽  
Rabih Hassan ◽  
Nancy Martinez ◽  
Sandra L. Giannini ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Regulatory Region ◽  
Variable Region ◽  
Immunoglobulin Heavy Chain ◽  
Physical Interaction ◽  
Heavy Chain Variable Region

A transcription factor which binds to the enhancers of SV40, immunoglobulin heavy chain and U2 snRNA genes

Nature ◽  
1987 ◽  
Vol 325 (6101) ◽  
pp. 268-272 ◽  
Author(s):  
Dirk Bohmann ◽  
Walter Keller ◽  
Trevor Dale ◽  
Hans R. Schöler ◽  
Graham Tebb ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Heavy Chain ◽  
Immunoglobulin Heavy Chain ◽  
U2 Snrna

scholarly journals Inhibition of Nuclear Import by Protein Kinase B (Akt) Regulates the Subcellular Distribution and Activity of the Forkhead Transcription Factor AFX

2001 ◽  
Vol 21 (10) ◽  
pp. 3534-3546 ◽  
Author(s):  
Amy M. Brownawell ◽  
Geert J. P. L. Kops ◽  
Ian G. Macara ◽  
Boudewijn M. T. Burgering
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Nuclear Localization ◽  
Nuclear Export ◽  
Transcriptional Activity ◽  
Protein Kinase B ◽  
Phosphorylation Site ◽  
Nuclear Accumulation ◽  
Forkhead Transcription Factor ◽  
Akt Phosphorylation

ABSTRACT AFX belongs to a subfamily of Forkhead transcription factors that are phosphorylated by protein kinase B (PKB), also known as Akt. Phosphorylation inhibits the transcriptional activity of AFX and changes the steady-state localization of the protein from the nucleus to the cytoplasm. Our goal was threefold: to identify the cellular compartment in which PKB phosphorylates AFX, to determine whether the nuclear localization of AFX plays a role in regulating its transcriptional activity, and to elucidate the mechanism by which phosphorylation alters the localization of AFX. We show that phosphorylation of AFX by PKB occurs in the nucleus. In addition, nuclear export mediated by the export receptor, Crm1, is required for the inhibition of AFX transcriptional activity. Both phosphorylated and unphosphorylated AFX, however, bind Crm1 and can be exported from the nucleus. These results suggest that export is unregulated and that phosphorylation by PKB is not required for the nuclear export of AFX. We show that AFX enters the nucleus by an active, Ran-dependent mechanism. Amino acids 180 to 221 of AFX comprise a nonclassical nuclear localization signal (NLS). S193, contained within this atypical NLS, is a PKB-dependent phosphorylation site on AFX. Addition of a negative charge at S193 by mutating the residue to glutamate reduces nuclear accumulation. PKB-mediated phosphorylation of AFX, therefore, attenuates the import of the transcription factor, which shifts the localization of the protein from the nucleus to the cytoplasm and results in the inhibition of AFX transcriptional activity.

The gene encoding human TFE3, a transcription factor that binds the immunoglobulin heavy-chain enhancer, maps to Xp11.22

Genomics ◽  
1991 ◽  
Vol 11 (2) ◽  
pp. 374-378 ◽  
Author(s):  
Paula S. Henthorn ◽  
Christine C. Stewart ◽  
Tom Kadesch ◽  
Jennifer M. Puck
Keyword(s):  
Transcription Factor ◽  
Heavy Chain ◽  
Immunoglobulin Heavy Chain ◽  
Gene Encoding

scholarly journals Variegated Expression of the Endogenous Immunoglobulin Heavy-Chain Gene in the Absence of the Intronic Locus Control Region

1999 ◽  
Vol 19 (10) ◽  
pp. 7031-7040 ◽  
Author(s):  
Diana Ronai ◽  
Maribel Berru ◽  
Marc J. Shulman
Keyword(s):  
Heavy Chain ◽  
Half Life ◽  
Single Cells ◽  
Insertion Site ◽  
Immunoglobulin Heavy Chain ◽  
Inhibitory Effect ◽  
Chain Gene ◽  
Heavy Chain Gene ◽  
Cell Divisions ◽  
The Stability

ABSTRACT The expression of chromosomally integrated transgenes usually varies greatly among independent transfectants. This variability in transgene expression has led to the definition of locus control regions (LCRs) as elements which render expression consistent. Analyses of expression in single cells revealed that the expression of transgenes which lack an LCR is often variegated, i.e., on in some cells and off in others. In many cases, transgenes which show variegated expression were found to have inserted near the centromere. These observations have suggested that the LCR prevents variegation by blocking the inhibitory effect of heterochromatin and other repetitive-DNA-containing structures at the insertion site and have raised the question of whether the LCR plays a similar role in endogenous genes. To address this question, we have examined the effects of deleting the LCR from the immunoglobulin heavy-chain locus of a mouse hybridoma cell line in which expression of the immunoglobulin μ heavy-chain gene is normally highly stable. Our analysis of μ expression in single cells shows that deletion of this LCR resulted in variegated expression of the μ gene. That is, in the absence of the LCR, expression of the μ gene in the recombinant locus could be found in either of two epigenetically maintained, metastable states, in which transcription occurred either at the normal rate or not at all. In the absence of the LCR, the on state had a half-life of ∼100 cell divisions, while the half-life of the off state was ∼40,000 cell divisions. For recombinants with an intact LCR, the half-life of the on state exceeded 50,000 cell divisions. Our results thus indicate that the LCR increased the stability of the on state by at least 500-fold.

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