PRAJA is overexpressed in glioblastoma and contributes to neural precursor development

Abstract

PRAJA, a RING-H2 E3 ligase, is abundantly expressed in brain tissues such as the cerebellum and frontal cortex, amongst others, and more specifically in neural progenitor cells as well as in multiple cancers that include glioblastomas. However, the specific role that Praja plays in neural development and gliomas remains unclear. In this investigation, we performed bioinformatic analyses to examine Praja1 and Praja2 expression across 29 cancer types, and observed raised levels of Praja1 and Praja2 in gliomas with an inverse relationship between Praja1 and apoptotic genes and Praja substrates such as Smad3. We analyzed the role of Praja in the developing brain through loss of function studies, using morpholinos targeting Praja1 in embryonic zebrafish, and observed that Praja1 is expressed prominently in regions enriched with neural precursor cell subtypes. Antisense Praja morpholinos resulted in multiple embryonic defects including delayed neural development likely through increased apoptosis. Further studies revealed high levels of Cdk1 with loss of Praja1 in TGF-β or insulin treated cells, supporting the link between Praja1 and cell cycle regulation. In summary, these studies underscore Praja's role in mammalian brain development and Praja1 deregulation may lead to gliomas possibly through the regulation of cell cycle and/or apoptosis.

CIC protein instability contributes to tumorigenesis in glioblastoma

“…Knockdown of CIC in U87-shPJA1 cells reversed the reduced proliferation caused by PJA1 knockdown, consistent with a role for a PJA1–CIC axis in GBM. PJA1 expression at the mRNA level was highest in glioma compared to the spectrum of TCGA samples (Figure S5F), which is consistent with recently published findings showing PJA1-overexpression in GBM 50 , further highlighting the importance of PJA1 in GBM and likely in other Ras-driven tumors and providing an opportunity for therapeutic exploration in this aggressive tumor.…”

PJA1 Coordinates with the SMC5/6 Complex To Restrict DNA Viruses and Episomal Genes in an Interferon-Independent Manner

“…PJA1 (Praja1 or RNF70) is a RING-H2 domain E3 ubiquitin ligase expressed mainly in brain, liver, kidney, and embryo ( 5 , 6 ) and related to liver development and nervous system function ( 7 ). Deletion of PJA1 was observed in patients with craniofrontonasal syndrome and associated with mild learning disabilities ( 8 ), whereas overexpression of PJA1 facilitates skeletal myogenesis and contributes to neural precursor development ( 9 , 10 ). Several targets of PJA1-mediated polyubiquitination were identified, including Dlxin-1, Smad3, and PRC2 ( 11 – 13 ).…”

Genome-wide analysis of genes encoding core components of the ubiquitin system during cerebral cortex development

“…On average, Pja1 transcripts were 11- and 5–sixfold more abundant than Pja2 transcripts on E11-E13 and E17-PN1, respectively. The human and mouse Pja1 genes are highly expressed in the brain, particularly in the cerebral cortex [ 60 ]. Northern blot experiments showed Pja1 mRNA in the immature brain on E11.5.…”

“…Suppression of Pja1 expression led to a high apoptosis rate, indicating that the protein exerts a prosurvival anti-apoptotic effect. In line with the function of the encoded protein in cell survival, Pja1 mRNA has been previously found to be overexpressed in twenty-nine cancer types, with particularly high expression in gliomas [ 60 ]. Altogether, these results support the idea that Praja1 proteins play important roles in brain development and regulation of cell apoptosis.…”