Msx3 protein recruits histone deacetylase to down-regulate the Msx1 promoter

Msx1 promoter is known to be repressed by Msx1 protein [Shetty, Takahashi, Matsui, Iyengar and Raghow (1999) Biochem. J. 339, 751–758]. We show that in the transiently transfected C2C12 myoblasts, co-expression of Msx3 also causes potent repression of Msx1 promoter that can be relieved by exogenous expression of cAMP-response-element-binding protein-binding protein (CBP) and p300 in a dose-dependent manner. Co-immunoprecipitation and Western blot analyses revealed that Msx3 interacts with CBP and p300 and this interaction significantly decreases the histone acetyltransferase (HAT) activity of both proteins. We also discovered that Msx3-mediated repression of Msx1 promoter is synergized by the exogenous co-expression of histone deacetylase 1 (HDAC1). Furthermore, the repression of Msx1 promoter by Msx3 could be relieved by treating transfected cells with trichostatin A, an inhibitor of HDAC(s). Finally, we show that Msx3 and HDAC1 can be co-immunoprecipitated in a complex that does not contain CBP and that Msx3 and HDAC1 proteins are co-localized in the nucleus. Taken together, our results strongly suggest that two distinct multiprotein complexes are present within the nuclei of C2C12 cells: one containing Msx3 and HDAC(s) and another containing Msx3 and CBP and/or p300. On the basis of these results, we propose a dual mechanism of repression by Msx3 protein that involves the squelching of the HAT activity of co-activators, CBP and p300, and recruitment of HDAC(s).

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Recruitment of cAMP-response Element-binding Protein and Histone Deacetylase Has Opposite Effects on Glucocorticoid Receptor Gene Transcription

Journal of Biological Chemistry ◽

10.1074/jbc.m109.072728 ◽

2009 ◽

Vol 285 (7) ◽

pp. 4489-4510 ◽

Cited By ~ 21

Author(s):

Manjapra Variath Govindan

Keyword(s):

Glucocorticoid Receptor ◽

Histone Deacetylase ◽

Gene Transcription ◽

Binding Protein ◽

Receptor Gene ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Response Element ◽

Glucocorticoid Receptor Gene ◽

Element Binding Protein

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MMP28 gene expression is regulated by Sp1 transcription factor acetylation

Biochemical Journal ◽

10.1042/bj20091798 ◽

2010 ◽

Vol 427 (3) ◽

pp. 391-400 ◽

Cited By ~ 17

Author(s):

Tracey E. Swingler ◽

Lara Kevorkian ◽

Kirsty L. Culley ◽

Sara A. Illman ◽

David A. Young ◽

...

Keyword(s):

Histone Deacetylase Inhibitors ◽

Binding Protein ◽

Trichostatin A ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Receptor Associated Protein ◽

Sp1 Transcription Factor ◽

Basal Expression ◽

Element Binding Protein ◽

Interfering Rna

MMP-28 (epilysin) is a recently cloned member of the MMP (matrix metalloproteinase) family. It is highly expressed in the skin by keratinocytes, the developing and regenerating nervous system and a number of other normal human tissues, as well as a number of carcinomas. The MMP28 promoter has previously been cloned and characterized identifying a conserved GT-box that binds Sp1/Sp3 (specificity proteins 1 and 3) proteins and is essential for the basal expression of the gene. The present study demonstrates that MMP28 expression is induced by HDAC (histone deacetylase) inhibitors and that this effect is mediated through the GT-box. Transient transfection assays have shown that the induction of MMP28 expression by the HDAC inhibitior TSA (trichostatin A) is mediated via Sp1 at the GT-box. Immunoprecipitation experiments have shown that the acetylation of Sp1 and Sp3 is increased by TSA treatment; however, no effect on DNA binding was observed. Histone acetyltransferases such as p300 and P/CAF [p300/CREB (cAMP-response-element-binding protein)-binding protein-associated factor] increased induction of the MMP28 promoter by Sp1. Knockdown of HDAC1 using siRNA (small interfering RNA) also induces the MMP28 promoter. Oligonucleotide pulldown identified STRAP (serine/threonine kinase receptor-associated protein) as a further protein recruited to the MMP28 promoter and acting functionally with Sp1.

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Involvement of Transducer of Regulated cAMP Response Element-Binding Protein Activity on Corticotropin Releasing Hormone Transcription

Endocrinology ◽

10.1210/en.2009-0963 ◽

2010 ◽

Vol 151 (3) ◽

pp. 1109-1118 ◽

Cited By ~ 37

Author(s):

Ying Liu ◽

Ana G. Coello ◽

Valery Grinevich ◽

Greti Aguilera

Keyword(s):

Promoter Activity ◽

Nuclear Translocation ◽

Binding Protein ◽

Primary Cultures ◽

Camp Response Element Binding ◽

Neuronal Cultures ◽

Dependent Manner ◽

Camp Response Element ◽

Response Element ◽

Element Binding Protein

We have recently shown that phospho-cAMP response element-binding protein (CREB) is essential but not sufficient for activation of CRH transcription, suggesting the requirement of a coactivator. Here, we test the hypothesis that the CREB coactivator, transducer of regulated CREB activity (TORC), is required for activation of CRH transcription, using the cell line 4B and primary cultures of hypothalamic neurons. Immunohistochemistry and Western blot experiments in 4B cells revealed time-dependent nuclear translocation of TORC1,TORC 2, and TORC3 by forskolin [but not by the phorbol ester, phorbol 12-myristate 13-acetate (PMA)] in a concentration-dependent manner. In reporter gene assays, cotransfection of TORC1 or TORC2 potentiated the stimulatory effect of forskolin on CRH promoter activity but had no effect in cells treated with PMA. Knockout of endogenous TORC using silencing RNA markedly inhibited forskolin-activated CRH promoter activity in 4B cells, as well as the induction of endogenous CRH primary transcript by forskolin in primary neuronal cultures. Coimmunoprecipitation and chromatin immunoprecipitation experiments in 4B cells revealed association of CREB and TORC in the nucleus, and recruitment of TORC2 by the CRH promoter, after 20-min incubation with forskolin. These studies demonstrate a correlation between nuclear translocation of TORC with association to the CRH promoter and activation of CRH transcription. The data suggest that TORC is required for transcriptional activation of the CRH promoter by acting as a CREB coactivator. In addition, cytoplasmic retention of TORC during PMA treatment is likely to explain the failure of phorbolesters to activate CRH transcription in spite of efficiently phosphorylating CREB.

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Aberrant expression of cAMP-response-element-binding protein (‘CREB’) induces apoptosis

Biochemical Journal ◽

10.1042/bj3430249 ◽

1999 ◽

Vol 343 (1) ◽

pp. 249-255 ◽

Cited By ~ 13

Author(s):

Kumiko SAEKI ◽

Akira YUO ◽

Emiko SUZUKI ◽

Yoshio YAZAKI ◽

Fumimaro TAKAKU

Keyword(s):

Cell Cycle ◽

Expression Vector ◽

Binding Protein ◽

Camp Response Element Binding ◽

Dependent Manner ◽

Transactivation Domain ◽

Camp Response Element ◽

Response Element ◽

Element Binding Protein ◽

Induction Of Apoptosis

We have reported previously that cAMP-response-element-binding protein (CREB) was phosphorylated in a cell-cycle-dependent manner, showing that it was phosphorylated at early S-phase at casein kinase II target sites. To assess the possible involvement of CREB in cell cycle progression, CREB expression vector was transiently transfected into various cells. Unexpectedly we found that transfection with CREB expression vector resulted in an abundance of dead cells. Morphological examination revealed that these cells had undergone apoptosis. The coincidence of CREB overexpression and apoptosis induction at the individual cell level was confirmed by a immunohistochemical study. To confirm that overexpression of CREB was the cause of apoptosis, a dominant-negative mutant of CREB, KCREB, was co-expressed with the wild type. The co-existence of KCREB effectively rescued CREB-mediated apoptosis in a dose-dependent manner, verifying that apoptosis was truly a specific effect of overexpressed CREB and not an artifact of the transfection procedure. Deletion analysis indicates that neither the Q1 transactivation domain, which functions in transcription, nor the kinase-inducible domain, in which a cluster of various kinase targets exists, is necessary; however, the Q2 transactivation domain is required for the induction of apoptosis. A more precise study indicates that the four-residue stretch Glu-Glu-Ala-Ala at the most C-terminal region of the Q2 domain is especially important for the induction of apoptosis. Thus overexpressed CREB induces apoptosis by transmitting certain signals from the C-terminal portion of the Q2 domain. Possible roles of cell-cycle-regulated phosphorylation and also an elevation of the intracellular cAMP level in CREB-induced apoptosis are suggested.

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Faculty Opinions recommendation of Does cAMP response element-binding protein have a pivotal role in hippocampal synaptic plasticity and hippocampus-dependent memory?

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1014814.194668 ◽

2003 ◽

Author(s):

Yadin Dudai

Keyword(s):

Synaptic Plasticity ◽

Binding Protein ◽

Camp Response Element Binding ◽

Pivotal Role ◽

Camp Response Element ◽

Response Element ◽

Hippocampal Synaptic Plasticity ◽

Element Binding Protein ◽

Hippocampus Dependent Memory

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Faculty Opinions recommendation of Nuclear inositol 1,4,5-trisphosphate receptors regulate local Ca2+ transients and modulate cAMP response element binding protein phosphorylation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1027399.329527 ◽

2005 ◽

Author(s):

Thomas Cremer

Keyword(s):

Protein Phosphorylation ◽

Binding Protein ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Response Element ◽

Inositol 1,4,5 Trisphosphate ◽

Element Binding Protein

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Scutellarin Mitigates Cancer-Induced Bone Pain by Suppressing CaMKII/CREB Pathway in Rat Models

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.17:249-253 ◽

2019 ◽

Vol 17 (3) ◽

pp. 249-253

Author(s):

Liu Chenglong ◽

Liu Haihua ◽

Zhang Fei ◽

Zheng Jie ◽

Wei Fang

Keyword(s):

Protein Kinase ◽

Bone Pain ◽

Binding Protein ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Dependent Protein Kinase ◽

Response Element ◽

Protein Kinase Ii ◽

Element Binding Protein ◽

Dependent Protein

Cancer-induced bone pain is a severe and complex pain caused by metastases to bone in cancer patients. The aim of this study was to investigate the analgesic effect of scutellarin on cancer-induced bone pain in rat models by intrathecal injection of Walker 256 carcinoma cells. Mechanical allodynia was determined by paw withdrawal threshold in response to mechanical stimulus, and thermal hyperalgesia was indicated by paw withdrawal latency in response to noxious thermal stimulus. The paw withdrawal threshold and paw withdrawal latencies were significantly decreased after inoculation of tumor cells, whereas administration of scutellarin significantly attenuated tumor cell inoculation-induced mechanical and heat hyperalgesia. Tumor cell inoculation-induced tumor growth was also significantly abrogated by scutellarin. Ca2+/calmodulin-dependent protein kinase II is a multifunctional kinase with up-regulated activity in bone pain models. The activation of Ca2+/calmodulin-dependent protein kinase II triggers phosphorylation of cAMP-response element binding protein. Scutellarin significantly reduced the expression of phosphorylated-Ca2+/calmodulin-dependent protein kinase II and phosphorylated-cAMP-response element binding protein in cancer-induced bone pain rats. Collectively, our study demonstrated that scutellarin attenuated tumor cell inoculation-induced bone pain by down-regulating the expression of phosphorylated-Ca2+/calmodulin-dependent protein kinase II and phosphorylated-cAMP-response element binding protein. The suppressive effect of scutellarin on phosphorylated-Ca2+/calmodulin-dependent protein kinase II/phosphorylated-cAMP-response element binding protein activation may serve as a novel therapeutic strategy for CIBP management.

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