Nuclear Factor 1 and T-Cell Factor/LEF Recognition Elements Regulate <i>Pitx2</i> Transcription in Pituitary Development

Ai, Di; Wang, Jun; Amen, Melanie; Lu, Mei-Fang; Amendt, Brad A.; Martin, James F.

doi:10.1128/mcb.01848-06

Cited by 35 publications

(29 citation statements)

References 48 publications

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“…1 K-N). To gain insight into postnatal Pitx2 isoform expression, we investigated LacZ expression in a transgenic line, Pitx2c tg3K , in which LacZ is directed by Pitx2c regulatory elements (16). Because this Pitx2c transgene is influenced by copy number and position effect, this experiment provided only qualitative information about Pitx2 isoform expression in left atrium.…”

Section: Resultsmentioning

confidence: 99%

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Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification

Wang

Klysik

Sood³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Atrial fibrillation (AF), the most prevalent sustained cardiac arrhythmia, often coexists with the related arrhythmia atrial flutter (AFL). Limitations in effectiveness and safety of current therapies make an understanding of the molecular mechanism underlying AF more urgent. Genome-wide association studies implicated a region of human chromosome 4q25 in familial AF and AFL, ≈150 kb distal to the Pitx2 homeobox gene, a developmental left-right asymmetry (LRA) gene. To investigate the significance of the 4q25 variants, we used mouse models to investigate Pitx2 in atrial arrhythmogenesis directly. When challenged by programmed stimulation, Pitx2 null+/− adult mice had atrial arrhythmias, including AFL and atrial tachycardia, indicating that Pitx2 haploinsufficiency predisposes to atrial arrhythmias. Microarray and in situ studies indicated that Pitx2 suppresses sinoatrial node (SAN)-specific gene expression, including Shox2, in the left atrium of embryos and young adults. In vivo ChIP and transfection experiments indicated that Pitx2 directly bound Shox2 in vivo, supporting the notion that Pitx2 directly inhibits the SAN-specific genetic program in left atrium. Our findings implicate Pitx2 and Pitx2-mediated LRA-signaling pathways in prevention of atrial arrhythmias., the most common adult arrhythmia, increases in prevalence with age, eventually afflicting 5% of the population over age 65 years and 10% of those over age 80 years. Moreover, patients with AF have a significantly increased risk of stroke, heart failure, and dementia (1-3). Electrical impulses critical for a normal heartbeat are initiated in the sinoatrial node (SAN) or pacemaker region. In AF, rapid and irregular atrial activity overrides normal SAN function, often resulting in irregular impulse conduction to the ventricles. In many cases, ectopic electrical activity originates in the pulmonary veins and may serve to trigger and maintain AF (1, 4). The related arrhythmia, atrial flutter (AFL), displays more regular and organized electrical activity than does AF (5). Significantly, current treatments for AF are suboptimal because of incomplete effectiveness and deleterious side effects. It also has been recognized that untreated AF results in pathologic remodeling that makes AF more likely to recur (6). Thus, it is critically important to uncover the genetic mechanisms underlying AF to aid in patient management and to develop more safe and effective therapies.The pituitary homeobox (Pitx) family of homeobox genes containing three genes, Pitx1, Pitx2, and Pitx3, is a subgroup within the larger Paired-related superfamily of homeobox genes (7,8). Pitx2 was identified as the gene mutated in Rieger syndrome I, a haploinsufficient disorder that includes ocular, tooth, and anterior body wall defects as primary characteristics (9). Importantly, the Pitx2 gene encodes three isoforms: Pitx2a, Pitx2b, and Pitx2c. The Pitx2c isoform plays a critical role as a late effector in left-right asymmetry (LRA), a fundamental component of organ morphogenesis in vertebrate...

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Section: Resultsmentioning

confidence: 99%

“…The Pitx2 null allele, which removes function of all Pitx2 isoforms, and the Pitx2 tg3k transgenic line have been described previously (15,16).…”

Section: Methodsmentioning

confidence: 99%

Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification

Wang

Klysik

Sood³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

280

318

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“…In tumours, deregulation of the Wnt pathway leads to increased stability of b-catenin, which accumulates and translocates into the nucleus Morin et al, 1997). Nuclear b-catenin binds to members of the TCF/ LEF family, resulting in the transactivation of genes containing TBE in their promoter, such as CCND1 (Shtutman et al, 1999), AXIN2 (Jho et al, 2002;Lustig et al, 2002) or PITX2, a paired-related homeobox gene required for the development of several tissues (Kioussi et al, 2002;Ai et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

et al. 2011

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The DNp63 protein, a product of the TP63 gene that lacks the N-terminal domain, has a critical role in the maintenance of self renewal and progenitor capacity in several types of epithelial tissues. DNp63 is frequently overexpressed in squamous cell carcinoma (SCC) and in some other epithelial tumours. This overexpression may contribute to tumour progression through dominantnegative effects on the transcriptionally active (TA) isoforms of the p53 family (TAp63, TAp73 and p53), as well as through independent mechanisms. However, the molecular basis of DNp63 overexpression is not fully understood. Here, we show that the expression of DNp63 is regulated by the Wnt/b-catenin pathway in human hepatocellular carcinoma (HCC) and SCC cell lines. This regulation operates in particular through TCF/LEF sites present in the P2 promoter of TP63. In addition, we show that DNp63 and b-catenin are frequently coexpressed and accumulated in oesophageal SCC, but not in HCC. These results suggest that activation of the b-catenin pathway may contribute to overexpression of DNp63 during tumour progression, in a cell type-specific manner.

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“…The number of colonies derived from PITX2-knockdown cells was significantly decreased to 38% of that from non-silencing cells Wnt signaling. 9,[11][12][13][14][15] Pitx2 knockout mice die by embryonic day 15 due to severe developmental defects. 9 Mutations in the PITX2 gene have been linked to several human disorders, including Axenfeld-Rieger syndrome, iridogoniodysgenesis syndrome, and sporadic cases of Peters anomaly.…”

Section: Introductionmentioning

confidence: 99%

Pituitary homeobox 2 (PITX2) promotes thyroid carcinogenesis by activation of cyclin D2

Huang¹,

Guigon²,

Fan³

et al. 2010

Cell Cycle

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Nuclear Factor 1 and T-Cell Factor/LEF Recognition Elements Regulate Pitx2 Transcription in Pituitary Development

Cited by 35 publications

References 48 publications

Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification

Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

Pituitary homeobox 2 (PITX2) promotes thyroid carcinogenesis by activation of cyclin D2

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