scholarly journals Nuclear Pore Component Nup98 Is a Potential Tumor Suppressor and Regulates Posttranscriptional Expression of Select p53 Target Genes

2012 ◽  
Vol 48 (5) ◽  
pp. 799-810 ◽  
Author(s):  
Stephan Singer ◽  
Ruiying Zhao ◽  
Anthony M. Barsotti ◽  
Anette Ouwehand ◽  
Mina Fazollahi ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Target Genes ◽  
Nuclear Pore ◽  
P53 Target Genes ◽  
Potential Tumor Suppressor

CBFβ-SMMHC Inactivates p53 Tumor Suppressor Through Aberrant Protein Interaction and Recruitment of HDAC8

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 772-772
Author(s):  
Jing Qi ◽  
Sandeep Singh ◽  
Qi Cai ◽  
Hongjun Liu ◽  
Hieu Vu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Suppressor ◽  
Fusion Protein ◽  
Cell Line ◽  
Protein Interaction ◽  
Target Genes ◽  
P53 Protein ◽  
Knock Down ◽  
Aberrant Protein ◽  
P53 Target Genes

Abstract Abstract 772 Chromosomal inversion inv(16)(p13.1q22) is found in approximately 12% of acute myeloid leukemia (AML) patients, and leads to the fusion of the transcription factor gene CBFb and the MYH11 gene, and encodes a fusion protein CBFβ-SMMHC. Previous studies revealed that CBFβ-SMMHC is a dominant inhibitor of core-binding factor (CBF) function, and impairs hematopoietic differentiation. Expression of CBFβ-SMMHC predisposes for leukemia transformation, however, the molecular mechanism underlying the leukemogenic function of CBFβ-SMMHC remains elusive. The tumor suppressor p53 is considered the master genomic guardian that is frequently mutated in a wide variety of tumors but is rarely mutated in inv(16) AML. Thus, we examined whether CBFβ-SMMHC fusion protein might impair p53 function. We found that p53 acetylation (Ac-p53) level was reduced in the presence of CBFβ-SMMHC fusion protein in the myeloid progenitor 32D cell line as well as in primary pre-leukemic bone marrow progenitor cells isolated from our conditional Cbfb-MYH11 knock-in (Cbfb56M/+/Mx1-Cre) mice (Kuo et al, Cancer Cell 2006, 9:1,57-68). We assessed the effect of CBFβ-SMMHC on p53 transcriptional activity by quantitative RT-PCR analysis of p53 target genes including TP53 and p21 Cdkn1a, Mdm2, Bid, Bax, Stag1, LincRNA-p21, Gadd45b in 32D cells. The result showed that expression of these p53 target genes are reduced in the presence of CBFβ-SMMHC fusion protein, consistent with the impaired Ac-p53 by CBFβ-SMMHC. To understand how CBFβ-SMMHC impairs p53 function, we tested whether CBFβ-SMMHC fusion protein might interact with the p53 protein by co-immunoprecipitation (co-IP) assays. We found that CBFβ-SMMHC fusion protein interacts with p53 both in 32D cells and primary bone marrow cells. Although CBFβ-SMMHC fusion protein is detected both in the nucleus and the cytoplasm, the complex with p53 is present exclusively in the nucleus. It has been reported that CBFβ-SMMHC interacts with histone deacetylase 8 (HDAC8) through the C-terminal SMMHC region. Therefore, we assessed the interaction between CBFβ-SMMHC, p53 and HDAC8 in 32D cell line by co-IP and sequential co-IP. We were able to detect a multimeric protein complex containing CBFβ-SMMHC, p53, and Hdac8. To access whether HDAC8 contributes to the deacetylation of p53, we used two independent small-hairpin (sh)-RNA to knock-down Hdac8 in 32D-CBFβ-SMMHC cells. Hdac8 knock-down led to robust increase in Ac-p53 levels while total p53 levels were modestly stabilized. To test whether this effect is dependent on the deacetylase function of HDAC8, we used HDAC8 selective pharmacological inhibitors (HDAC8i including PCI-34051 and PCI-48012) directed against its catalytic sites (Balasubramanian et al Leukemia 2008, 22:5,1026-34). Treatment with HDAC8i remarkably increased Ac-p53 in both control and CBFβ-SMMHC cells. Since p53 protein levels were also increased upon HDAC8i treatment, we included Mdm2 inhibitor Nutlin-3 to stabilize p53. HDAC8i treatment alone or in combination with Nutlin-3 was able to enhance Ac-p53 compared to Nutlin-3 treatment, confirming its effect in restoring p53 acetylation. Collectively, our study shows that the CBFβ-SMMHC fusion protein forms an aberrant complex with p53 and HDAC8, leading to the aberrant deacetylation and impaired activity of p53. In addition, this deacetylation of p53 conferred by CBFβ-SMMHC is mediated by HDAC8. Our study reveals a novel leukemogenic mechanism in which CBFβ-SMMHC disrupts p53 activation through aberrant protein-protein interaction and recruitment of HDAC8. Disclosures: No relevant conflicts of interest to declare.

A nuclear pore component regulates select p53 target genes

2012 ◽  
Vol 50 (01) ◽  
Author(s):  
SR Singer ◽  
A Barsotti ◽  
M Fazollahi ◽  
A Ouwehand ◽  
D Grünwald ◽  
...  
Keyword(s):  
Target Genes ◽  
Nuclear Pore ◽  
P53 Target Genes

381: Promoter Hypermethylation Profile of Kidney Cancer with New Pro-Apoptotic P53 Target Genes and Possible Clinical Implications

2006 ◽  
Vol 175 (4S) ◽  
pp. 125-125
Author(s):  
Frank Christoph ◽  
Steffen Weikert ◽  
Carsten Kempkensteffen ◽  
Martin Schostak ◽  
Hans Krause ◽  
...  
Keyword(s):  
Kidney Cancer ◽  
Target Genes ◽  
Promoter Hypermethylation ◽  
Clinical Implications ◽  
P53 Target Genes

Potential tumor suppressor miR-1247 is down-regulated in CpG island methylator phenotype colon cancers

2012 ◽  
Vol 215 (3) ◽  
pp. S11
Author(s):  
Jennifer J. Liang ◽  
Kathryn L. DeJulius ◽  
Awad Jarrar ◽  
Angela Ting ◽  
James Church ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cpg Island ◽  
Cpg Island Methylator Phenotype ◽  
Colon Cancers ◽  
Methylator Phenotype ◽  
Potential Tumor Suppressor

scholarly journals RIZ1: a potential tumor suppressor in glioma

BMC Cancer ◽  
2015 ◽  
Vol 15 (1) ◽  
Author(s):  
Chenran Zhang ◽  
Qiubei Zhu ◽  
Hua He ◽  
Lei Jiang ◽  
Qiang Qiang ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Potential Tumor Suppressor

scholarly journals Evaluation of transcriptionally regulated genes identifies NCOR1 in hormone receptor negative breast tumors and lung adenocarcinomas as a potential tumor suppressor gene

PLoS ONE ◽  
2018 ◽  
Vol 13 (11) ◽  
pp. e0207776 ◽  
Author(s):  
María del Mar Noblejas-López ◽  
Sara Morcillo-García ◽  
Cristina Nieto-Jiménez ◽  
Miriam Nuncia-Cantarero ◽  
Balázs Győrffy ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Hormone Receptor ◽  
Breast Tumors ◽  
Suppressor Gene ◽  
Lung Adenocarcinomas ◽  
Potential Tumor Suppressor

scholarly journals CK1α ablation in keratinocytes induces p53-dependent, sunburn-protective skin hyperpigmentation

2017 ◽  
Vol 114 (38) ◽  
pp. E8035-E8044 ◽  
Author(s):  
Chung-Hsing Chang ◽  
Che-Jung Kuo ◽  
Takamichi Ito ◽  
Yu-Ya Su ◽  
Si-Tse Jiang ◽  
...  
Keyword(s):  
Target Genes ◽  
Neutralizing Antibody ◽  
Double Knockout ◽  
Melanocyte Stimulating Hormone ◽  
Kit Ligand ◽  
Skin Physiology ◽  
P53 Activation ◽  
P53 Target Genes ◽  
Single Knockout

Casein kinase 1α (CK1α), a component of the β-catenin destruction complex, is a critical regulator of Wnt signaling; its ablation induces both Wnt and p53 activation. To characterize the role of CK1α (encoded byCsnk1a1) in skin physiology, we crossed mice harboring floxedCsnk1a1with mice expressing K14–Cre–ERT2to generate mice in which tamoxifen induces the deletion ofCsnk1a1exclusively in keratinocytes [single-knockout (SKO) mice]. As expected, CK1α loss was accompanied by β-catenin and p53 stabilization, with the preferential induction of p53 target genes, but phenotypically most striking was hyperpigmentation of the skin, importantly without tumorigenesis, for at least 9 mo afterCsnk1a1ablation. The number of epidermal melanocytes and eumelanin levels were dramatically increased in SKO mice. To clarify the putative role of p53 in epidermal hyperpigmentation, we established K14–Cre–ERT2CK1α/p53 double-knockout (DKO) mice and found that coablation failed to induce epidermal hyperpigmentation, demonstrating that it was p53-dependent. Transcriptome analysis of the epidermis revealed p53-dependent up-regulation of Kit ligand (KitL). SKO mice treated with ACK2 (a Kit-neutralizing antibody) or imatinib (a Kit inhibitor) abrogated the CK1α ablation-induced hyperpigmentation, demonstrating that it requires the KitL/Kit pathway. Pro-opiomelanocortin (POMC), a precursor of α-melanocyte–stimulating hormone (α-MSH), was not activated in the CK1α ablation-induced hyperpigmentation, which is in contrast to the mechanism of p53-dependent UV tanning. Nevertheless, acute sunburn effects were successfully prevented in the hyperpigmented skin of SKO mice. CK1α inhibition induces skin-protective eumelanin but no carcinogenic pheomelanin and may therefore constitute an effective strategy for safely increasing eumelanin via UV-independent pathways, protecting against acute sunburn.

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