Zac1 (Lot1), a Potential Tumor Suppressor Gene, and the Gene for ɛ-Sarcoglycan Are Maternally Imprinted Genes: Identification by a Subtractive Screen of Novel Uniparental Fibroblast Lines

Abstract

Imprinted genes are expressed from one allele according to their parent of origin, and many are essential to mammalian embryogenesis. Here we show that the -sarcoglycan gene (Sgce) and Zac1 (Lot1) are both paternally expressed imprinted genes. They were identified in a subtractive screen for imprinted genes using a cDNA library made from novel parthenogenetic and wild-type fibroblast lines. Sgce is a component of the dystrophin-sarcoglycan complex, Zac1 is a nuclear protein inducing growth arrest and/or apoptosis, and Zac1 is a potential tumor suppressor gene. Sgce and Zac1 are expressed predominantly from their paternal alleles in all adult mouse tissues, except that Zac1 is biallelic in the liver and Sgce is weakly expressed from the maternal allele in the brain. Sgce and Zac1 are broadly expressed in embryos, with Zac1 being highly expressed in the liver primordium, the umbilical region, and the neural tube. Sgce, however, is strongly expressed in the allantoic region on day 9.5 but becomes more widely expressed throughout the embryo by day 11.5. Sgce is located at the proximal end of mouse chromosome 6 and is a candidate gene for embryonic lethality associated with uniparental maternal inheritance of this region. Zac1 maps to the proximal region of chromosome 10, identifying a new imprinted locus in the mouse, homologous with human chromosome 6q24-q25. In humans, unipaternal disomy for this region is associated with fetal growth retardation and transient neonatal diabetes mellitus. In addition, loss of expression of ZAC has been described for a number of breast and ovarian carcinomas, suggesting that ZAC is a potential tumor suppressor gene.

Calcr, a brain-specific imprinted mouse calcitonin receptor gene in the imprinted cluster of the proximal region of chromosome 6

“…Four imprinted genes have previously been isolated from this region in human and mouse (Piras et al 2000;Ono et al 2001;Mizuno et al 2002;Okita et al 2003). Calcr was localized close to these genes, indicating that it was a new member of this imprinted cluster (Fig.…”

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

“…In cerebellar granule cells, exposed to different neurotoxic challenges, Lot1 was not affected by purely apoptotic cell death, while it was transiently induced by mixed necrotic-apoptotic cell death . Lot1/Zac1 was broadly expressed in embryos, being highly expressed in the liver primordium, the umbilical region, and the neural tube (Piras et al, 2000). Comparative analysis of the expression profiles of the three Plag family members in developing nervous system of mouse showed that these genes are expressed in both unique and overlapping patterns in the central and peripheral nervous systems, and in olfactory and neuroendocrine lineages (Alam et al, 2005).…”

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

“…Because loss of Zac1 expression has been reported in a number of tumor types including breast and ovary cancers, melanomas, astrocytomas, and renal cell carcinomas, it has been proposed that Zac1 acts as a tumor suppressor gene (2)(3)(4)(5)(6). In contrast, recent studies have unveiled another role for Zac1 in the etiology of transient neonatal diabetes mellitus.…”