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The role of KRAS splice variants in cancer biology

Cristina Nuevo-Tapioles1, Mark R Philips1

  • 1Perlmutter Cancer Center, NYU School of Medicine, New York, NY, United States.

Frontiers in Cell and Developmental Biology
|November 17, 2022
PubMed

Insights

KRAS, a key cancer oncogene, produces two splice variants, KRAS4A and KRAS4B. Emerging research highlights KRAS4A

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The RAS family of genes, including HRAS, NRAS, and KRAS, are crucial in cancer biology.
  • KRAS is the most frequently mutated oncogene in human cancers.
  • KRAS pre-mRNA splicing yields two distinct protein isoforms, KRAS4A and KRAS4B, differing in C-terminal membrane targeting sequences.

Purpose of the Study:

  • To review the characteristics and differential functions of KRAS splice variants.
  • To explore the role of KRAS variants in cancer initiation and progression.
  • To highlight the understudied KRAS4A isoform and its emerging functions.

Main Methods:

  • Literature review of studies on KRAS splice variants.
  • Analysis of functional differences between KRAS4A and KRAS4B.
  • Examination of KRAS variant expression in cancer.
  • Investigation of KRAS4A's role in regulating cellular metabolism.

Main Results:

  • Both KRAS4A and KRAS4B are oncogenic when KRAS is mutated.
  • KRAS4A has non-overlapping functions with KRAS4B, including regulation of hexokinase 1.
  • Expression of KRAS4A is confirmed in cancer, suggesting its importance.
  • Differential expression of splice variants may influence metabolic vulnerabilities in KRAS-mutant tumors.

Conclusions:

  • KRAS splice variants possess distinct functions relevant to cancer.
  • KRAS4A's role in cancer biology is increasingly recognized.
  • Understanding KRAS variant-specific functions is critical for targeted cancer therapies.
  • Metabolic reprogramming in KRAS-mutant cancers may depend on splice variant ratios.
Keywords:
KRASKRAS4AKRAS4Balternative splicingglycolysisoncogeneoncoprotein

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