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Article ; Online: Acetylation Increases EWS-FLI1 DNA Binding and Transcriptional Activity.

Schlottmann, Silke / Erkizan, Hayriye V / Barber-Rotenberg, Julie S / Knights, Chad / Cheema, Amrita / Uren, Aykut / Avantaggiati, Maria L / Toretsky, Jeffrey A

Frontiers in oncology

2012 Volume 2, Page(s) 107

Abstract: Ewing Sarcoma (ES) is associated with a balanced chromosomal translocation that in most cases leads to the expression of the oncogenic fusion protein and transcription factor EWS-FLI1. EWS-FLI1 has been shown to be crucial for ES cell survival and tumor ... ...

Abstract	Ewing Sarcoma (ES) is associated with a balanced chromosomal translocation that in most cases leads to the expression of the oncogenic fusion protein and transcription factor EWS-FLI1. EWS-FLI1 has been shown to be crucial for ES cell survival and tumor growth. However, its regulation is still enigmatic. To date, no functionally significant post-translational modifications of EWS-FLI1 have been shown. Since ES are sensitive to histone deacetylase inhibitors (HDI), and these inhibitors are advancing in clinical trials, we sought to identify if EWS-FLI1 is directly acetylated. We convincingly show acetylation of the C-terminal FLI1 (FLI1-CTD) domain, which is the DNA binding domain of EWS-FLI1. In vitro acetylation studies showed that acetylated FLI1-CTD has higher DNA binding activity than the non-acetylated protein. Over-expression of PCAF or treatment with HDI increased the transcriptional activity of EWS-FLI1, when co-expressed in Cos7 cells. However, our data that evaluates the acetylation of full-length EWS-FLI1 in ES cells remains unclear, despite creating acetylation specific antibodies to four potential acetylation sites. We conclude that EWS-FLI1 may either gain access to chromatin as a result of histone acetylation or undergo regulation by direct acetylation. These data should be considered when patients are treated with HDAC inhibitors. Further investigation of this phenomenon will reveal if this potential acetylation has an impact on tumor response.
Language	English
Publishing date	2012-09-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X ; 2234-943X
ISSN (online)	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2012.00107
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Article: Defective p53 post-translational modification required for wild type p53 inactivation in malignant epithelial cells with mdm2 gene amplification.

Knights, Chad D / Liu, Yuangang / Appella, Ettore / Kulesz-Martin, Molly

The Journal of biological chemistry

2003 Volume 278, Issue 52, Page(s) 52890–52900

Abstract: Mdm2 gene amplification occurs in benign and chemotherapy-responsive malignant tumors with wtp53 genes as well as in breast and epithelial cancers. Mdm2 amplification in benign tumors suggests that it is not sufficient for p53 inactivation in cancer, ... ...

Abstract	Mdm2 gene amplification occurs in benign and chemotherapy-responsive malignant tumors with wtp53 genes as well as in breast and epithelial cancers. Mdm2 amplification in benign tumors suggests that it is not sufficient for p53 inactivation in cancer, implying that other defects in the p53 pathway are required for malignancy. We investigated mechanisms of wtp53 protein inactivation in malignant conversion of epithelial cells by comparing clonally related initiated cells with their derivative cancerous cells that have mdm2 amplification. Deficiencies in p53 accumulation and activities in response to DNA damage were not due simply to Mdm2 destabilization of p53 protein, but to continued association of DNA-bound p53 with Mdm2 protein and lack of binding and acetylation by p300 protein. The aberrant interactions were not because of mdm2 amplification alone, because DNA-bound p53 protein from initiated cells failed to bind ectopically expressed Mdm2 or endogenous overexpressed Mdm2 from cancerous cells. Phosphorylations of endogenous p53 at Ser18, -23, or -37 were insufficient to dissociate Mdm2, because each was induced by UV in cancerous cells. Interestingly, phospho-mimic p53-T21E did dissociate the Mdm2 protein from DNA-bound p53 and recovered p300 binding and p21 induction in the cancerous cells. Thus wtp53 in malignant cells with mdm2 amplification can be inactivated by continued association of DNA-bound p53 protein with Mdm2 and failure of p300 binding and acetylation, coupled with a defect in p53 phosphorylation at Thr21. These findings suggest therapeutic strategies that address both p53/Mdm2 interaction and associated p53 protein defects in human tumors that have amplified mdm2 genes.
MeSH term(s)	Acetyltransferases/metabolism ; Animals ; Cell Cycle Proteins/metabolism ; Cell Differentiation ; Cell Line ; Cell Line, Transformed ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; DNA/metabolism ; DNA Damage ; DNA, Complementary/metabolism ; Dose-Response Relationship, Radiation ; Epithelial Cells/metabolism ; Flow Cytometry ; Gene Amplification ; Genes, Reporter ; Genes, p53 ; Green Fluorescent Proteins ; HSP70 Heat-Shock Proteins/metabolism ; Histone Acetyltransferases ; Humans ; Immunoblotting ; Luminescent Proteins/metabolism ; Mice ; Nuclear Proteins ; Phosphorylation ; Plasmids/metabolism ; Precipitin Tests ; Protein Binding ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins c-mdm2 ; Proto-Oncogene Proteins p21(ras)/metabolism ; Threonine/chemistry ; Time Factors ; Transcription Factors ; Transcriptional Activation ; Transfection ; Tumor Suppressor Protein p53/chemistry ; Tumor Suppressor Protein p53/metabolism ; Ultraviolet Rays ; p300-CBP Transcription Factors
Chemical Substances	Cell Cycle Proteins ; DNA, Complementary ; HSP70 Heat-Shock Proteins ; Luminescent Proteins ; Nuclear Proteins ; Proto-Oncogene Proteins ; Transcription Factors ; Tumor Suppressor Protein p53 ; Green Fluorescent Proteins (147336-22-9) ; Threonine (2ZD004190S) ; DNA (9007-49-2) ; Acetyltransferases (EC 2.3.1.-) ; Histone Acetyltransferases (EC 2.3.1.48) ; p300-CBP Transcription Factors (EC 2.3.1.48) ; p300-CBP-associated factor (EC 2.3.1.48) ; MDM2 protein, human (EC 2.3.2.27) ; Mdm2 protein, mouse (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; HRAS protein, human (EC 3.6.5.2) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2003-10-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M300279200
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Article: Repression of transcription and interference with DNA binding of TATA-binding protein by C-terminal alternatively spliced p53.

Huang, Hua / Kaku, Shinsuke / Knights, Chad / Park, Byung / Clifford, Jane / Kulesz-Martin, Molly

Experimental cell research

2002 Volume 279, Issue 2, Page(s) 248–259

Abstract: The protein encoded by C-terminal alternatively spliced p53 mRNA (p53as) has been shown previously to occur naturally in mouse cells and to bind sequence-specifically to DNA more efficiently than p53 (p53r, regular form). In the current study, p53as and ... ...

Abstract	The protein encoded by C-terminal alternatively spliced p53 mRNA (p53as) has been shown previously to occur naturally in mouse cells and to bind sequence-specifically to DNA more efficiently than p53 (p53r, regular form). In the current study, p53as and p53r proteins ectopically expressed in p53-deficient cells each transactivated reporter plasmids containing p53 binding sites. However, p53as consistently was more efficient in transcriptional repression of promoters lacking p53 binding sites and in concentration-dependent repression of the p21(WAF1/Cip-l/Sdi) promoter sequence. The p53as protein, like p53r, associated with TATA-binding protein (TBP), indicating that this interaction does not require the last 26 amino acids of p53. Consistent with its stronger repression effects, p53as interfered with TBP binding to a TATA-containing DNA sequence more efficiently than p53r protein. Taken together, these in vitro and in vivo results demonstrate a novel role in transcriptional repression for a naturally occurring C-terminal variant form of mouse p53 protein associated with differences in DNA binding properties and interference with transcription factor binding.
MeSH term(s)	Alternative Splicing ; Animals ; Cell Line ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/genetics ; Cyclins/metabolism ; DNA/metabolism ; DNA-Binding Proteins/metabolism ; Enzyme Inhibitors/metabolism ; Gene Expression Regulation ; Genes, Reporter ; Mice ; Promoter Regions, Genetic ; TATA Box ; TATA-Box Binding Protein ; Transcription Factors/metabolism ; Transcription, Genetic ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Cdkn1a protein, mouse ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins ; DNA-Binding Proteins ; Enzyme Inhibitors ; TATA-Box Binding Protein ; Transcription Factors ; Tumor Suppressor Protein p53 ; DNA (9007-49-2)
Language	English
Publishing date	2002-10-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1006/excr.2002.5596
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Article: The tumor suppressor protein p53 is required for neurite outgrowth and axon regeneration.

Di Giovanni, Simone / Knights, Chad D / Rao, Mahadev / Yakovlev, Alexander / Beers, Jeannette / Catania, Jason / Avantaggiati, Maria Laura / Faden, Alan I

The EMBO journal

2006 Volume 25, Issue 17, Page(s) 4084–4096

Abstract: Axon regeneration is substantially regulated by gene expression and cytoskeleton remodeling. Here we show that the tumor suppressor protein p53 is required for neurite outgrowth in cultured cells including primary neurons as well as for axonal ... ...

Abstract	Axon regeneration is substantially regulated by gene expression and cytoskeleton remodeling. Here we show that the tumor suppressor protein p53 is required for neurite outgrowth in cultured cells including primary neurons as well as for axonal regeneration in mice. These effects are mediated by two newly identified p53 transcriptional targets, the actin-binding protein Coronin 1b and the GTPase Rab13, both of which associate with the cytoskeleton and regulate neurite outgrowth. We also demonstrate that acetylation of lysine 320 (K320) of p53 is specifically involved in the promotion of neurite outgrowth and in the regulation of the expression of Coronin 1b and Rab13. Thus, in addition to its recognized role in neuronal apoptosis, surprisingly, p53 is required for neurite outgrowth and axonal regeneration, likely through a different post-translational pathway. These observations may suggest a novel therapeutic target for promoting regenerative responses following peripheral or central nervous system injuries.
MeSH term(s)	Acetylation ; Animals ; Axons/physiology ; Cells, Cultured ; Cytoskeleton/physiology ; Lysine/metabolism ; Male ; Mice ; Microfilament Proteins/metabolism ; Nerve Regeneration/physiology ; Neurites/physiology ; Neurons/physiology ; Neurons/ultrastructure ; Rats ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Protein p53/physiology ; rab GTP-Binding Proteins/metabolism
Chemical Substances	Microfilament Proteins ; Tumor Suppressor Protein p53 ; coronin proteins (145420-64-0) ; Rab13 protein, mouse (EC 3.6.1.-) ; rab GTP-Binding Proteins (EC 3.6.5.2) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2006-09-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.1038/sj.emboj.7601292
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Article ; Online: Functional mimicry of the acetylated C-terminal tail of p53 by a SUMO-1 acetylated domain, SAD.

Cheema, Amrita / Knights, Chad D / Rao, Mahadev / Catania, Jason / Perez, Ricardo / Simons, Brigitte / Dakshanamurthy, Sivanesan / Kolukula, Vamsi K / Tilli, Maddalena / Furth, Priscilla A / Albanese, Christopher / Avantaggiati, Maria Laura

Journal of cellular physiology

2010 Volume 225, Issue 2, Page(s) 371–384

Abstract: The ubiquitin-like molecule, SUMO-1, a small protein essential for a variety of biological processes, is covalently conjugated to many intracellular proteins, especially to regulatory components of the transcriptional machinery, such as histones and ... ...

Abstract	The ubiquitin-like molecule, SUMO-1, a small protein essential for a variety of biological processes, is covalently conjugated to many intracellular proteins, especially to regulatory components of the transcriptional machinery, such as histones and transcription factors. Sumoylation provides either a stimulatory or an inhibitory signal for proliferation and for transcription, but the molecular mechanisms by which SUMO-1 achieves such versatility of effects are incompletely defined. The tumor suppressor and transcription regulator p53 is a relevant SUMO-1 target. Particularly, the C-terminal tail of p53 undergoes both sumoylation and acetylation. While the effects of sumoylation are still controversial, acetylation modifies p53 interaction with chromatin embedded promoters, and enforces p53 apoptotic activity. In this study, we show that the N-terminal region of SUMO-1 might functionally mimic this activity of the p53 C-terminal tail. We found that this SUMO-1 domain possesses similarity with the C-terminal acetylable p53 tail as well as with acetylable domains of other transcription factors. SUMO-1 is, indeed, acetylated when conjugated to its substrates and to p53. In the acetylable form SUMO-1 tunes the p53 response by modifying p53 transcriptional program, by promoting binding onto selected promoters and by favoring apoptosis. By contrast, when non-acetylable, SUMO-1 enforces cell-cycle arrest and p53 binding to a different sets of genes. These data demonstrate for the first time that SUMO-1, a post-translational modification is, in turn, modified by acetylation. Further, they imply that the pleiotropy of effects by which SUMO-1 influences various cellular outcomes and the activity of p53 depends upon its acetylation state.
MeSH term(s)	Acetylation ; Adenocarcinoma/metabolism ; Amino Acid Sequence ; Animals ; Apoptosis ; Mice ; Mice, Transgenic ; Protein Conformation ; Protein Structure, Tertiary ; SUMO-1 Protein/genetics ; SUMO-1 Protein/metabolism ; Submandibular Gland Neoplasms/metabolism ; Transcription Factors ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	SUMO-1 Protein ; Transcription Factors ; Tumor Suppressor Protein p53
Language	English
Publishing date	2010-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.22224
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Article ; Online: Restoration of DNA-binding and growth-suppressive activity of mutant forms of p53 via a PCAF-mediated acetylation pathway.

Perez, Ricardo E / Knights, Chad D / Sahu, Geetaram / Catania, Jason / Kolukula, Vamsi K / Stoler, Daniel / Graessmann, Adolf / Ogryzko, Vasily / Pishvaian, Michael / Albanese, Christopher / Avantaggiati, Maria Laura

Journal of cellular physiology

2010 Volume 225, Issue 2, Page(s) 394–405

Abstract: Tumor-derived mutant forms of p53 compromise its DNA binding, transcriptional, and growth regulatory activity in a manner that is dependent upon the cell-type and the type of mutation. Given the high frequency of p53 mutations in human tumors, ... ...

Abstract	Tumor-derived mutant forms of p53 compromise its DNA binding, transcriptional, and growth regulatory activity in a manner that is dependent upon the cell-type and the type of mutation. Given the high frequency of p53 mutations in human tumors, reactivation of the p53 pathway has been widely proposed as beneficial for cancer therapy. In support of this possibility p53 mutants possess a certain degree of conformational flexibility that allows for re-induction of function by a number of structurally different artificial compounds or by short peptides. This raises the question of whether physiological pathways for p53 mutant reactivation also exist and can be exploited therapeutically. The activity of wild-type p53 is modulated by various acetyl-transferases and deacetylases, but whether acetylation influences signaling by p53 mutant is still unknown. Here, we show that the PCAF acetyl-transferase is down-regulated in tumors harboring p53 mutants, where its re-expression leads to p53 acetylation and to cell death. Furthermore, acetylation restores the DNA-binding ability of p53 mutants in vitro and expression of PCAF, or treatment with deacetylase inhibitors, promotes their binding to p53-regulated promoters and transcriptional activity in vivo. These data suggest that PCAF-mediated acetylation rescues activity of at least a set of p53 mutations. Therefore, we propose that dis-regulation of PCAF activity is a pre-requisite for p53 mutant loss of function and for the oncogenic potential acquired by neoplastic cells expressing these proteins. Our findings offer a new rationale for therapeutic targeting of PCAF activity in tumors harboring oncogenic versions of p53.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Proliferation ; Chromatin/metabolism ; Colorectal Neoplasms/metabolism ; DNA/metabolism ; Humans ; Mice ; Mutation ; Protein Binding ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; p300-CBP Transcription Factors/genetics ; p300-CBP Transcription Factors/metabolism
Chemical Substances	Chromatin ; Tumor Suppressor Protein p53 ; DNA (9007-49-2) ; p300-CBP Transcription Factors (EC 2.3.1.48) ; p300-CBP-associated factor (EC 2.3.1.48)
Language	English
Publishing date	2010-06-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.22285
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Article: Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate.

Knights, Chad D / Catania, Jason / Di Giovanni, Simone / Muratoglu, Selen / Perez, Ricardo / Swartzbeck, Amber / Quong, Andrew A / Zhang, Xiaojing / Beerman, Terry / Pestell, Richard G / Avantaggiati, Maria Laura

The Journal of cell biology

2006 Volume 173, Issue 4, Page(s) 533–544

Abstract: The activity of the p53 gene product is regulated by a plethora of posttranslational modifications. An open question is whether such posttranslational changes act redundantly or dependently upon one another. We show that a functional interference between ...

Abstract	The activity of the p53 gene product is regulated by a plethora of posttranslational modifications. An open question is whether such posttranslational changes act redundantly or dependently upon one another. We show that a functional interference between specific acetylated and phosphorylated residues of p53 influences cell fate. Acetylation of lysine 320 (K320) prevents phosphorylation of crucial serines in the NH(2)-terminal region of p53; only allows activation of genes containing high-affinity p53 binding sites, such as p21/WAF; and promotes cell survival after DNA damage. In contrast, acetylation of K373 leads to hyperphosphorylation of p53 NH(2)-terminal residues and enhances the interaction with promoters for which p53 possesses low DNA binding affinity, such as those contained in proapoptotic genes, leading to cell death. Further, acetylation of each of these two lysine clusters differentially regulates the interaction of p53 with coactivators and corepressors and produces distinct gene-expression profiles. By analogy with the "histone code" hypothesis, we propose that the multiple biological activities of p53 are orchestrated and deciphered by different "p53 cassettes," each containing combination patterns of posttranslational modifications and protein-protein interactions.
MeSH term(s)	Acetylation ; Amino Acid Sequence/physiology ; Apoptosis/genetics ; Binding Sites/genetics ; Cell Cycle/genetics ; Cell Line, Tumor ; Cell Survival/genetics ; Cell Transformation, Neoplastic/genetics ; Gene Expression Regulation/genetics ; Genes, cdc/physiology ; Humans ; Lysine/metabolism ; Phosphorylation ; Promoter Regions, Genetic/genetics ; Protein Binding/genetics ; Protein Processing, Post-Translational/genetics ; Protein Structure, Tertiary/physiology ; Regulatory Elements, Transcriptional/genetics ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Tumor Suppressor Protein p53/chemistry ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Repressor Proteins ; Tumor Suppressor Protein p53 ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2006-05-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.200512059
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Article: Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate

Knights, Chad D / Catania, Jason / Giovanni, Simone Di / Muratoglu, Selen / Perez, Ricardo / Swartzbeck, Amber / Quong, Andrew A / Zhang, Xiaojing / Beerman, Terry / Pestell, Richard G / Avantaggiati, Maria Laura

Journal of cell biology. 2006 May 22, v. 173, no. 4

2006

Abstract	The activity of the p53 gene product is regulated by a plethora of posttranslational modifications. An open question is whether such posttranslational changes act redundantly or dependently upon one another. We show that a functional interference between specific acetylated and phosphorylated residues of p53 influences cell fate. Acetylation of lysine 320 (K320) prevents phosphorylation of crucial serines in the NH₂-terminal region of p53; only allows activation of genes containing high-affinity p53 binding sites, such as p21/WAF; and promotes cell survival after DNA damage. In contrast, acetylation of K373 leads to hyperphosphorylation of p53 NH₂-terminal residues and enhances the interaction with promoters for which p53 possesses low DNA binding affinity, such as those contained in proapoptotic genes, leading to cell death. Further, acetylation of each of these two lysine clusters differentially regulates the interaction of p53 with coactivators and corepressors and produces distinct gene-expression profiles. By analogy with the "histone code" hypothesis, we propose that the multiple biological activities of p53 are orchestrated and deciphered by different "p53 cassettes," each containing combination patterns of posttranslational modifications and protein-protein interactions.
Language	English
Dates of publication	2006-0522
Size	p. 533-544.
Publishing place	The Rockefeller University Press
Document type	Article
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
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