Aberrant DNA demethylation in promoter region and aberrant expression of mRNA of PAX4 gene in hematologic malignancies

Li, Yinghua; Nagai, Hirokazu; Ohno, Toshihito; Ohashi, Haruhiko; Murohara, Toyoaki; Saito, Hidehiko; Kinoshita, Tomohiro

doi:10.1016/j.leukres.2006.04.001

Cited by 18 publications

(18 citation statements)

References 25 publications

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“…Furthermore, aberrant DNA demethylation in the promoter region of the pax4 gene was recently associated with induced expression of the transcript and development of haematologic malignancies (Li et al, 2006). These results clearly implicate the transcription factor in tumorigenesis.…”

Section: Introductionmentioning

confidence: 83%

The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells

Brun¹,

Duhamel²,

He³

et al. 2007

Oncogene

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The paired/homeodomain transcription factor Pax4 is essential for islet b-cell generation during pancreas development and their survival in adulthood. High Pax4 expression was reported in human insulinomas indicating that deregulation of the gene may be associated with tumorigenesis. We report that rat insulinoma INS-1E cells express 25-fold higher Pax4 mRNA levels than rat islets. In contrast to primary b-cells, activin A but not betacellulin or glucose induced Pax4 mRNA levels indicating dissociation of Pax4 expression from insulinoma cell proliferation. Short hairpin RNA adenoviral constructs targeted to the paired domain or homeodomain (viPax4PD and viPax4HD) were generated. Pax4 mRNA levels were lowered by 73 and 50% in cells expressing either viPax4PD or viPax4HD. Transcript levels of the Pax4 target gene bcl-xl were reduced by 53 and 47%, whereas Pax6 and Pdx1 mRNA levels were unchanged. viPax4PD-infected cells displayed a twofold increase in spontaneous apoptosis and were more susceptible to cytokine-induced cell death. In contrast, proliferation was unaltered. RNA interference-mediated repression of insulin had no adverse effects on either Pax4 or Pdx1 expression as well as on cell replication or apoptosis. These results indicate that Pax4 is redundant for proliferation of insulinoma cells, whereas it is essential for survival through upregulation of the antiapoptotic gene bcl-xl.

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Section: Introductionmentioning

confidence: 83%

The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells

Brun¹,

Duhamel²,

He³

et al. 2007

Oncogene

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“…Mutations in this gene are associated with obesity, tumorigenesis, and metastasis (Tzimas et al, 2005). The PAX4 gene, located in 7q32, is a member of the paired box family of transcription factor that mediates differentiation of insulin-producing beta-cells in the pancreas and plays critical roles during cancer growth (Li et al, 2006). EGFR is a transmembrane glycoprotein that functions as a tyrosine protein kinase (Kondo and Shimizu, 1983).…”

Section: Discussionmentioning

confidence: 99%

Candidate gene polymorphisms for diabetes mellitus, cardiovascular disease and cancer are associated with longevity in Koreans

Park

Choi

et al. 2009

Exp Mol Med

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Abbreviations: ABCC8, ATP-binding cassette, sub-family C (CFTR/ MRP), member 8; ACE, angiotensin I converting enzyme (peptidyldipeptidase A) 1; ADCY2, adenylate cyclase 2 (brain); ALDH2, aldehyde dehydrogenase 2 family (mitochondrial); APOE, apolipoprotein E; CDK10, cyclin-dependent kinase 10; CETP, cholesteryl ester transfer protein, plasma; CI, confidence interval; CR, call rate; CVD, cardiovascular disease; DM, diabetes mellitus; HWE, Hardy-Weinberg equilibrium; IL12RB2, interleukin 12 receptor, beta 2; LD, linkage disequilibrium; LRM, logistic regression model; LYN, V-yes-1 Yamaguchi sarcoma viral related oncogene homolog; MAF, minor allele frequency; MGP, matrix Gla protein; MTTP, microsomal triglyceride transfer protein; OR, odds ratio; PAX4, paired box 4; PCSK1, convertase subtilisin/kexin type 1; PON1, paraoxonase 1; PPP1R14C, protein phosphatase 1, regulatory (inhibitor) subunit 14C; PPP1R1A, protein phosphatase 1, regulatory (inhibitor) subunit 1A; SNP, single nucleotide polymorphism; TNFSF11, tumor necrosis factor (ligand) superfamily, member 11 AbstractLong-lived people may have a unique genetic makeup that makes them more resistant than the general population to prevalent age-related diseases; however, not much is known about genes involved in the longevity. To identify susceptibility variants controlling longevity, we performed a high-throughput candidate gene study using 137 Koreans over 90 yr old and 213 young healthy Koreans. We evaluated 463 informative markers located in 176 candidate genes mostly for diabetes mellitus, cardiovascular disease and cancer under five genetic models. We estimated the odds ratios for each allele, genotype, haplotype, and gene-gene interaction using logistic regression analysis. Associations between 13 genes and longevity were detected at a P-value less than 0.01. Particularly, the rs671 (A) allele of the aldehyde dehydrogenase 2 family (mitochondrial) (ALDH2) gene was associated with longevity only in men (OR 2.11, P = 0.008). Four genes, proprotein convertase subtilisin/kexin type 1 (PCSK1, P = 0.008), epidermal growth factor receptor (EGFR, P = 0.003), paired box 4 (PAX4, P = 0.008), and V-yes-1 Yamaguchi sarcoma viral related oncogene homolog (LYN, P = 0.002) consistently yielded statistical evidence for association with longevity. The findings of the current study may provide a starting point for future studies to unravel genetic factors controlling longevity in Koreans.

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“…Treatment of rat islets with a DNA-methyltransferase inhibitor, 5′AZA, stimulates endogenous Pax4 expression and consequently expression of its downstream target Bcl-xL , suggesting that demethylation of Pax4 promoter is an epigenetic modification controlling Pax4 expression [34]. Moreover, demethylation of the human PAX4 promoter region located −1347 to −1103 bp from translation initiation site (Figure 2A) has been linked to aberrant expression of PAX4 in lymph nodes of patients with diffuse large B cell lymphoma (DLBCL) as well as in several hematological cell lines [73]. Of note, hematological organs do not express PAX4 under physiological conditions.…”

Section: Pax4 Regulationmentioning

confidence: 99%

The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences

Lorenzo

Juárez-Vicente

Cobo-Vuilleumier

et al. 2017

Genes

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Paired box 4 (PAX4) is a key factor in the generation of insulin producing β-cells during embryonic development. In adult islets, PAX4 expression is sequestered to a subset of β-cells that are prone to proliferation and more resistant to stress-induced apoptosis. The importance of this transcription factor for adequate pancreatic islets functionality has been manifested by the association of mutations in PAX4 with the development of diabetes, independently of its etiology. Overexpression of this factor in adult islets stimulates β-cell proliferation and increases their resistance to apoptosis. Additionally, in an experimental model of autoimmune diabetes, a novel immunomodulatory function for this factor has been suggested. Altogether these data pinpoint at PAX4 as an important target for novel regenerative therapies for diabetes treatment, aiming at the preservation of the remaining β-cells in parallel to the stimulation of their proliferation to replenish the β-cell mass lost during the progression of the disease. However, the adequate development of such therapies requires the knowledge of the molecular mechanisms controlling the expression of PAX4 as well as the downstream effectors that could account for PAX4 action.

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Aberrant DNA demethylation in promoter region and aberrant expression of mRNA of PAX4 gene in hematologic malignancies

Cited by 18 publications

References 25 publications

The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells

The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells

Candidate gene polymorphisms for diabetes mellitus, cardiovascular disease and cancer are associated with longevity in Koreans

The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences

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