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 ).…”

Targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth

“…By regulating cAMP signaling, praja2 efficiently couples phosphorylation to ubiquitination of protein kinases, scaffolds, and effectors, with important implications for neuronal activity, development, inflammatory responses, ciliogenesis, cell growth, and metabolism 18 – 28 . Dysregulation of praja2-regulated signaling pathways has been causally linked to the growth and progression of GBM 29 , 30 . In GBM cells, praja2 ubiquitylates and degrades MOB1, which is the regulatory subunit of LATS1/2 kinase and the positive regulator of the oncosuppressive Hippo pathway.…”