The cell cycle control gene ZAC/PLAGL1 is imprinted--a strong candidate gene for transient neonatal diabetes

Kamiya, Mamoru; Judson, Hannah; Okazaki, Yasushi; Kusakabe, Moriaki; Muramatsu, Masami; Takada, Shuji; Takagi, Nobuo; Arima, Takahiro; Wake, Norio; Kamimura, Katsunori; Satomura, Kenichi; Hermann, Róbert; Bonthron, David T.; Hayashizaki, Yoshihide

doi:10.1093/hmg/9.3.453

Cited by 199 publications

(147 citation statements)

References 31 publications

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“…Analysis of the CpG islands in the TNDM critical region for the presence of methylation differences between maternal and paternal alleles, using DNA from TNDM patients with paternal UPD 6 and normal controls, suggested LOT1/ZAC1 as a candidate imprinted gene for this disease (Gardner et al, 2000). Simultaneously, in another report, parthenogenetic DNA from the chimeric patient FD (patient with chimerism between normal or biparental and parthenogenetic cells) and androgenetic DNA from hydatidiform mole were compared to screen for imprinted genes, using restriction landmark genome scanning for methylation (Kamiya et al, 2000). The study resulted in identification of ZAC/PLAGL1/LOT1 as an imprinted gene and confirmed that this gene is expressed only from the paternal allele in a variety of tissues.…”

Section: Imprinting and Chromosomal Duplicationmentioning

confidence: 99%

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Abdollahi

2006

Journal Cellular Physiology

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Lost-on-transformation 1 (LOT1) (PLAGL1/ZAC1) is a member of the novel subfamily of zinc-finger transcription factors, designated as PLAG family. The other members in this group include PLAG1 and PLAGL2, which share high homology with each other and with LOT1, particularly in their zinc-finger amino-terminal region. They are structurally similar but functionally different. For example, the LOT1 gene encodes a growth suppressor protein and is localized on human chromosome 6q24-25, a chromosomal region that is frequently deleted in many types of human cancers. The gene is maternally imprinted and is linked to developmental disorders such as growth retardation and transient neonatal diabetes mellitus (TNDM). LOT1 is a target of growth factor signaling pathway(s) and silenced by epigenetic mechanisms, as well as by the loss of heterozygosity in different tumor tissues. PLAG1 is a protooncogene that is localized on chromosome 8q12 and was found to be a target of several types of chromosomal rearrangement including the one identified in pleomorphic adenomas of the salivary gland. Since the discovery of the PLAG family members in 1997, much has been learned about their structure and function, as are summarized in this review. While the available data suggest that these proteins may play important roles in regulating normal physiological functions in the mammals, a great deal more about their signaling pathway(s), potential role in the complex pathologies such as cancer and developmental disorders, and functional relationship between different family members and splice variants still remains to be uncovered.

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Section: Imprinting and Chromosomal Duplicationmentioning

confidence: 99%

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Abdollahi

2006

Journal Cellular Physiology

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“…In a previous study [3] the minimal region of duplication was refined to 440 kb, containing four protein-coding genes and one non-coding RNA. Among these, two have been confirmed to be imprinted, namely PLAGL1 (also known as ZAC or LOT1) [5] and HYMAI [6].…”

Section: Introductionmentioning

confidence: 99%

Further refinement of the critical minimal genetic region for the imprinting disorder 6q24 transient neonatal diabetes

et al. 2010

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Aims/hypothesis Transient neonatal diabetes (TND) is associated with overexpression of genes within a critical region on 6q24. This study aims to refine the boundaries of this region to reduce the number of potential candidate genes for 6q24 TND. Methods Fifteen patients with transient neonatal diabetes and submicroscopic chromosome 6 duplications were investigated. The duplications were confirmed by microsatellite analysis and subsequently mapped using tiled chromosome 6 array Comparative Genomic Hybridisation (aCGH) and MLPA. Duplication boundaries were compared to identify the minimal shared region of duplication.These data were then used with available clinical data to identify associations between size of 6q24 duplication and severity of TND phenotype. Results Alignment of the minimal region of duplication to the human genome reduced the minimal TND critical region, formerly estimated at 440 kb, to 160-173 kb, revealing PLAGL1 (pleiomorphic adenoma gene-like 1) and HYMAI (imprinted in hydatidiform mole) to be the only genes wholly included therein. Additionally, the complete paternal duplication of a region containing the theoretical protein FAM164B was associated with the severe growth restriction observed in 6q24 duplication patients. Conclusions/interpretation This study has significantly reduced the critical region associated with 6q24 TND. It has eliminated several previous TND candidate genes, leaving the overlapping imprinted genes PLAGL1 and HYMAI as the only remaining complete candidate genes for 6q24 TND. Moreover, these data provide the first evidence that an additional region, encompassing the theoretical protein FAM164B, may have a critical role in the growth restriction phenotype observed in many 6q24 TND patients.

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“…In contrast, recent studies have unveiled another role for Zac1 in the etiology of transient neonatal diabetes mellitus. This is a rare form of childhood diabetes which usually resolves in the first 6 months of life but strongly predisposes individuals to adult-onset type 2 diabetes (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Modulation of the Cyclin-Dependent Kinase Inhibitor p21WAF1/Cip1 Gene by Zac1 through the Antagonistic Regulators p53 and Histone Deacetylase 1 in HeLa Cells

Liu

Chan

Lin

et al. 2008

Molecular Cancer Research

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Zac1 is a novel seven -zinc finger protein which possesses the ability to bind specifically to GC-rich DNA elements. Zac1 not only promotes apoptosis and cell cycle arrest but also acts as a transcriptional cofactor for p53 and a number of nuclear receptors. Our previous study indicated that the enhancement of p53 activity by Zac1 is much more pronounced in HeLa cells compared with other cell lines tested. This phenomenon might be due to the coactivator effect of Zac1 on p53 and the ability of Zac1 to reverse E6 inhibition of p53. In the present study, we showed that Zac1 acted synergistically with either p53 or a histone deacetylase inhibitor, trichostatin A, to enhance p21 WAF1/Cip1 promoter activity. We showed that Zac1 physically interacted with some nuclear receptor corepressors such as histone deacetylase 1 (HDAC1) and mSin3a, and the induction of p21 WAF1/Cip1 gene and protein by Zac1 was suppressed by either overexpressing HDAC1 or its deacetylase-dead mutant. In addition, our data suggest that trichostatin A -induced p21 WAF1/Cip1 protein expression might be mediated through a p53-independent and HDAC deacetylaseindependent pathway. Taken together, our data suggest that Zac1 might be involved in regulating the p21 WAF1/Cip1 gene and protein expression through its protein-protein interaction with p53 and HDAC1 in HeLa cells.

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The cell cycle control gene ZAC/PLAGL1 is imprinted--a strong candidate gene for transient neonatal diabetes

Cited by 199 publications

References 31 publications

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Further refinement of the critical minimal genetic region for the imprinting disorder 6q24 transient neonatal diabetes

Modulation of the Cyclin-Dependent Kinase Inhibitor p21WAF1/Cip1 Gene by Zac1 through the Antagonistic Regulators p53 and Histone Deacetylase 1 in HeLa Cells

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