Inactivation of CREB mediated gene transcription by HDAC8 bound protein phosphatase

Gao, Junyuan; Siddoway, Benjamin; Huang, Qing; Xia, Houhui

doi:10.1016/j.bbrc.2008.11.135

Cited by 62 publications

(56 citation statements)

References 27 publications

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“…One possible explanation for these results could be that these pathways are not involved in CREB activation in MM cells as opposed to normal mesothelial cells. Alternatively, endogenously activated CREB in MM cells might be a result of constitutively inhibited protein phosphatase 1, a serine/ threonine phosphatase required to inactivate CREB by dephosphorylation, 36 in these cells. For example, microarray data from our laboratory suggests that several human MM cell lines have significantly lower levels of protein phosphatase 1 in comparison with nonmalignant human mesothelial cells (Shukla et al, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Activated cAMP Response Element Binding Protein Is Overexpressed in Human Mesotheliomas and Inhibits Apoptosis

Shukla

Bosenberg

MacPherson

et al. 2009

The American Journal of Pathology

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Little is known about the cellular mechanisms contributing to the development and chemoresistance of malignant mesothelioma (MM), an aggressive asbestos-associated tumor. A human mesothelial cell line (LP9/TERT-1) and isolated human pleural mesothelial cells showed rapid and protracted asbestos-induced cAMP response element binding protein (CREB1) phosphorylation, which was inhibited in LP9/TERT-1 cells by small molecule inhibitors of epidermal growth factor receptor phosphorylation and protein kinase A. Asbestos increased expression of several CREB target genes (c-FOS, EGR-1, MKP1, BCL2, and MMP13) and apoptosis, which was enhanced using small interfering CREB. Human MM tissue arrays showed elevated endogenous levels of phosphorylated nuclear CREB1 as compared with reactive mesothelial hyperplasias and normal lung tissue. Significantly increased phosphorylated CREB1 and mRNA levels of BCL2, c-FOS, MMP9, and MMP13 were also observed in MM cells in vitro, which were further augmented after addition of Doxorubicin (Dox). Small interfering CREB inhibited migration of MMs, increased apoptosis by Dox , and decreased BCL2 and BCL-xL expression , suggesting a role for these molecules in CREB-induced MM survival. These data indicate that CREB1 and its target genes are upregulated in asbestos-exposed human mesothelial cells through an epidermal growth factor receptor/ protein kinase A pathway. Since activated CREB1 also is increased endogenously in human MM and modifies migration and resistance to Dox-induced apoptosis , inhibition of CREB1 may be a new strategy for MM therapy.

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Section: Discussionmentioning

confidence: 99%

Activated cAMP Response Element Binding Protein Is Overexpressed in Human Mesotheliomas and Inhibits Apoptosis

Shukla

Bosenberg

MacPherson

et al. 2009

The American Journal of Pathology

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“…Despite these facts, little is known about the role of HDAC8 in the CNS. Additional insights come from the role of HDAC8 as a regulator of cAMP response element-binding (CREB)-dependent gene expression [68]. CREB target genes are essential in diverse processes such as glucose metabolism, cell survival, and neuronal plasticity (for review, see [69]).…”

Section: Hdac8mentioning

confidence: 99%

Multiple roles of class I HDACs in proliferation, differentiation, and development

Reichert

Choukrallah

Matthias

2012

Cell. Mol. Life Sci.

156

148

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Class I Histone deacetylases (HDACs) play a central role in controlling cell cycle regulation, cell differentiation, and tissue development. These enzymes exert their function by deacetylating histones and a growing number of non-histone proteins, thereby regulating gene expression and several other cellular processes. Class I HDACs comprise four members: HDAC1, 2, 3, and 8. Deletion and/or overexpression of these enzymes in mammalian systems has provided important insights about their functions and mechanisms of action which are reviewed here. In particular, unique as well as redundant functions have been identified in several paradigms. Studies with small molecule inhibitors of HDACs have demonstrated the medical relevance of these enzymes and their potential as therapeutic targets in cancer and other pathological conditions. Going forward, better understanding the specific role of individual HDACs in normal physiology as well as in pathological settings will be crucial to exploit this protein family as a useful therapeutic target in a range of diseases. Further dissection of the pathways they impinge on and of their targets, in chromatin or otherwise, will form important avenues of research for the future.

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“…Recently, it has been shown that PP1 can be targeted to CREB1, for efficient dephosphorylation, through binding of PP1 to HDAC1 (Canettieri et al, 2003) or HDAC8 proteins (Gao et al, 2009). HDACs catalyze the removal of acetyl groups from core histones (Marks et al, 2001), inducing local condensation of chromatin.…”

Section: Ccdc6 Physically Interacts With Hdac1mentioning

confidence: 99%

CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1

et al. 2010

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RET/papillary thyroid carcinoma 1 (PTC1) oncogene is frequently activated in human PTCs. It is characterized by the fusion of the intracellular kinase-encoding domain of RET to the first 101 amino acids of CCDC6. The aim of our work is to characterize the function of the CCDC6 protein to better understand the function of its truncation, that results in the loss of the expression of one allele, in the process of thyroid carcinogenesis. Here, we report that CCDC6 interacts with CREB1 and represses its transcriptional activity by recruiting histone deacetylase 1 and protein phosphatase 1 proteins at the CRE site of the CREB1 target genes. Finally, we show an increased CREB1 phosphorylation and activity in PTCs carrying the RET/PTC1 oncogene. Consistently, an increased expression of two known CREB1 target genes, AREG and cyclin A, was observed in this subgroup of thyroid papillary carcinomas. Therefore, the repression of CREB1 activity by CCDC6 has a critical function in the development of human thyroid papillary carcinomas carrying RET/PTC1 activation.

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Inactivation of CREB mediated gene transcription by HDAC8 bound protein phosphatase

Cited by 62 publications

References 27 publications

Activated cAMP Response Element Binding Protein Is Overexpressed in Human Mesotheliomas and Inhibits Apoptosis

Activated cAMP Response Element Binding Protein Is Overexpressed in Human Mesotheliomas and Inhibits Apoptosis

Multiple roles of class I HDACs in proliferation, differentiation, and development

CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1

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