English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

The rearrangement of pre-existing genes has long been thought of as the major mode of new gene generation. Recently,  de novo  gene birth from non-genic DNA was found to be an alternative mechanism to generate novel protein-coding genes. However, its functional role in human disease remains largely unknown. Here we show that  NCYM , a  cis -antisense gene of the  MYCN  oncogene, initially thought to be a large non-coding RNA, encodes a  de novo  evolved protein regulating the pathogenesis of human cancers, particularly neuroblastoma. The  NCYM  gene is evolutionally conserved only in the taxonomic group containing humans and chimpanzees. In primary human neuroblastomas,  NCYM  is 100% co-amplified and co-expressed with  MYCN , and  NCYM  mRNA expression is associated with poor clinical outcome. MYCN directly transactivates both  NCYM  and  MYCN  mRNA, whereas NCYM stabilizes MYCN protein by inhibiting the activity of GSK3β, a kinase that promotes MYCN degradation. In contrast to  MYCN  transgenic mice, neuroblastomas in  MYCN/NCYM  double transgenic mice were frequently accompanied by distant metastases, behavior reminiscent of human neuroblastomas with  MYCN  amplification. The NCYM protein also interacts with GSK3β, thereby stabilizing the MYCN protein in the tumors of the  MYCN / NCYM  double transgenic mice. Thus, these results suggest that GSK3β inhibition by NCYM stabilizes the MYCN protein both  in vitro  and  in vivo . Furthermore, the survival of  MYCN  transgenic mice bearing neuroblastoma was improved by treatment with NVP-BEZ235, a dual PI3K/mTOR inhibitor shown to destabilize MYCN via GSK3β activation. In contrast, tumors caused in  MYCN/NCYM  double transgenic mice showed chemo-resistance to the drug. Collectively, our results show that NCYM is the first  de novo  evolved protein known to act as an oncopromoting factor in human cancer, and suggest that  de novo  evolved proteins may functionally characterize human disease.

plos genetics

NCYM, a Cis-Antisense Gene of MYCN, Encodes a De Novo Evolved Protein That Inhibits GSK3β Resulting in the Stabilization of MYCN in Human Neuroblastomas