Tip60 Protein Isoforms and Altered Function in Skin and Tumors that Overexpress Ornithine Decarboxylase

Hobbs, Cheryl A.; Wei, Gang; DeFeo, Karen; Paul, Barry; Hayes, Candace S.; Gilmour, Susan K.

doi:10.1158/0008-5472.can-06-0359

Cited by 32 publications

(27 citation statements)

References 46 publications

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“…Tip60 also enhances c-Myc-transforming activity mediated by human T-cell lymphotropic virus type 1 (HTLV-1) pX splicevariant p30II and may contribute to adult T-cell leukemogenesis [Awasthi et al, 2005]. One recent report showed that Tip60 may be involved in polyamine-mediated tumor promotion [Hobbs et al, 2006]. Whether Tip60 modulates these transforming events through similar mechanisms described in the current study requires further investigation.…”

Section: Discussionsupporting

confidence: 51%

Tip60 modulates PLAGL2‐mediated transactivation by acetylation

Ning

Zheng

2007

J of Cellular Biochemistry

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Pleiomorphic adenoma gene (PLAG) family proteins are oncogenes involved in various malignancies including lipoblastomas, hepatoblastomas, and acute myeloid leukemia. Overexpression of PLAGL2 induces cell transformation and proliferation, but little is known about how its activities are regulated. We previously showed that transcriptional activity of PLAGL2 is negatively regulated by sumoylation. Here we report that Tip60 modulates PLAGL2 functions through acetylation. Tip60 associates with PLAGL2 through its zinc finger domain and acetylates PLAGL2. Wild-type but not the histone acetyltransferase (HAT)-minus mutant form of Tip60 enhances PLAGL2-mediated transactivation. In addition, coexpression of Tip60 and PLAGL2 completely abolishes the sumoylation of PLAGL2. Both Tip60 and DN-Ubc9 increase transactivation activity of wild-type but not the sumoylation deficient form of PLAGL2 (K250, 269, 356R), indicating that Tip60 acetylates PLAGL2 and abolishes the sumoylation of PLAGL2 possibly through modification of the same lysine residues (K250, 269, 356) within PLAGL2. Tip60 effects vary between different PLAGL2 target gene promoters, suggesting that Tip60 is a novel promoter-specific coactivator of PLAGL2. This is the first demonstration that Tip60 can function as a sumoylation inhibitor in part through its intrinsic acetyltransferase activity to regulate specific gene expression.

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Section: Discussionsupporting

confidence: 51%

Tip60 modulates PLAGL2‐mediated transactivation by acetylation

Ning

Zheng

2007

J of Cellular Biochemistry

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“…Our studies show that the activation of ATM and phosphorylation of the ATM substrates p53 and gH2AX are induced in both K6/ODC transgenic skin and in ODCoverexpressing primary keratinocytes. In addition, previous studies have shown that levels of the Tip60 HAT enzyme, reported to acetylate and activate ATM (30), are also substantially elevated in the skin of ODC-overexpressing mice (31).…”

Section: Discussionmentioning

confidence: 90%

Elevated Ornithine Decarboxylase Levels Activate Ataxia Telangiectasia Mutated–DNA Damage Signaling in Normal Keratinocytes

Wei

DeFeo²,

Hayes³

et al. 2008

Cancer Research

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We examined the effect of increased expression of ornithine decarboxylase (ODC), a key rate-limiting enzyme in polyamine biosynthesis, on cell survival in primary cultures of keratinocytes isolated from the skin of K6/ODC transgenic mice (Ker/ ODC) and their normal littermates (Ker/Norm). Although elevated levels of ODC and polyamines stimulate proliferation of keratinocytes, Ker/ODC undergo apoptotic cell death within days of primary culture unlike Ker/Norm that continue to proliferate. Phosphorylation of ataxia telangiectasia mutated (ATM) and its substrate p53 are significantly induced both in Ker/ODC and in K6/ODC transgenic skin. Chromatin immunoprecipitation analyses show that the increased level of p53 in Ker/ODC is accompanied by increased recruitment of p53 to the Bax proximal promoter. ATM activation is polyamine dependent because A-difluoromethylornithine, a specific inhibitor of ODC activity, blocks its phosphorylation. Ker/ ODC also displays increased generation of H 2 O 2 , acroleinlysine conjugates, and protein oxidation products as well as polyamine-dependent DNA damage, as measured by the comet assay and the expression of the phosphorylated form of the histone variant ;H2AX. Both reactive oxygen species generation and apoptotic cell death of Ker/ODC may, at least in part, be due to induction of a polyamine catabolic pathway that generates both H 2 O 2 and cytotoxic aldehydes, because spermine oxidase (SMO) levels are induced in Ker/ODC. In addition, treatment with MDL 72,527, an inhibitor of SMO, blocks the production of H 2 O 2 and increases the survival of Ker/ODC. These results show a novel activation of the ATM-DNA damage signaling pathway in response to increased ODC activity in nontumorigenic keratinocytes. [Cancer Res 2008;68(7):2214-22]

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“…By increasing the cell's chances of survival in the face of DNA damage that would normally result in the initiation of the cell death programme, this can lead to malignancy. On the other hand, upregulation of Tip60 has also been recently linked to promotion of epithelial tumorigenesis (Hobbs et al, 2006).…”

Section: Tip60 and Cancermentioning

confidence: 99%

The MYST family of histone acetyltransferases and their intimate links to cancer

2007

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The histone acetyltransferases (HATs) of the MYST family are highly conserved in eukaryotes and carry out a significant proportion of all nuclear acetylation. These enzymes function exclusively in multisubunit protein complexes whose composition is also evolutionarily conserved. MYST HATs are involved in a number of key nuclear processes and play critical roles in genespecific transcription regulation, DNA damage response and repair, as well as DNA replication. This suggests that anomalous activity of these HATs or their associated complexes can easily lead to severe cellular malfunction, resulting in cell death or uncontrolled growth and malignancy. Indeed, the MYST family HATs have been implicated in several forms of human cancer. This review summarizes the current understanding of these enzymes and their normal function, as well as their established and putative links to oncogenesis.

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Tip60 Protein Isoforms and Altered Function in Skin and Tumors that Overexpress Ornithine Decarboxylase

Cited by 32 publications

References 46 publications

Tip60 modulates PLAGL2‐mediated transactivation by acetylation

Tip60 modulates PLAGL2‐mediated transactivation by acetylation

Elevated Ornithine Decarboxylase Levels Activate Ataxia Telangiectasia Mutated–DNA Damage Signaling in Normal Keratinocytes

The MYST family of histone acetyltransferases and their intimate links to cancer

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