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

Abstract

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.

Promoter hypermethylation ofCDH1,FHIT,MTAPandPLAGL1in gastric adenocarcinoma in individuals from Northern Brazil

“…However, PLAGL1 has been described as a maternal imprinted gene and hypermethylation leads to transcriptional silencing, as reported in other neoplasias [41] . Considered an imprinted gene, we found PLAGL1 hypermethylation in 33.9% of GC and 7.7% of nonneoplastic gastric samples (Table 3).…”

Adenovirus vectors differentially modulate proliferation of pituitary lactotrophs in primary culture in a mitogen and infection time-dependent manner

“…We investigated whether the influence of adenovirus vectors on estrogen effects was mediated by a change in the response to estrogen of estrogen-responsive genes. We measured, in adenovirusinfected cells, E 2 -induced expression levels of various estrogen-responsive pituitary cell genes that regulate proliferation (Hennighausen et al 1997, Obaya et al 1999, Deneen et al 2003, Durand et al 2004, Abdollahi 2007. The E 2 responsiveness of mRNA levels of the estrogen-upregulated gene Pim3 and the estrogen-downregulated gene Plagl1 was not altered by adenovirus vectors, the response of the upregulated gene c-myc and downregulated gene Serpine1 was attenuated, and that of Stat5a was enhanced.…”

PLAGL1 protein is differentially expressed in the nephron segments and collecting ducts in human kidney

“…Many transcript variants encoding two main PLAGL1 isoforms (44.7 and 50.8 kDa) were found for this gene (Ensembl ENSG00000118495). PLAGL1 is ubiquitously expressed in a number of normal embryonic and adult tissues [1,2]. Studies performed so far allowed to determine PLAGL1 as a factor contributing to the regulation of cell growth and differentiation in several physiological and pathological processes.…”

“…It was shown that PLAGL1 -/-knock-out mice demonstrated fetal growth retardation, altered bone formation and neonatal mortality [3]. In the course of the embryonic development an increased PLAGL1 expression was detected in the nervous system, chondrogenic tissue, liver, myocardium and skeletal system [2]. The studies on the transient neonatal diabetes mellitus (TNDM) indicate the role of the PLAGL1 gene overexpression in etiopathogenesis of this disease [4,5].…”

“…inhibits cell growth and promotes cell cycle arrest [6,7]. PLAGL1 gene deletion as well as decrease of its expression were found in many types of human neoplasms: breast and ovarian cancers, basocellular skin cancer and adrenal gland tumors [1,2].…”