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. J. Cell. Physiol. 210: 16–25, 2007.