Limited proteolysis of cyclooxygenase-2 enhances cell proliferation

Esraa Saadi, Rapita Sood, Ido Dromi, Ranin Srouji, Ossama Abu Hatoum, Sharon Tal, Liza Barki-Harrington

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Accumulating evidence suggests that the cyclooxygenase-2 (COX-2) enzyme has additional catalytic-independent functions. Here we show that COX-2 appears to be cleaved in mouse and human tumors, which led us to hypothesize that COX-2 proteolysis may play a role in cell proliferation. The data presented herein show that a K598R point mutation at the carboxyl-terminus of COX-2 causes the appearance of several COX-2 immunoreactive fragments in nuclear compartments, and significantly enhances cell proliferation. In contrast, insertion of additional mutations at the border of the membrane-binding and catalytic domains of K598R COX-2 blocks fragment formation and prevents the increase in proliferation. Transcriptomic analyses show that K598R COX-2 significantly affects the expression of genes involved in RNA metabolism, and subsequent proteomics suggest that it is associated with proteins that regulate mRNA processing. We observe a similar increase in proliferation by expressing just that catalytic domain of COX-2 (ΔNT-COX-2), which is completely devoid of catalytic activity in the absence of its other domains. Moreover, we show that the ΔNT-COX-2 protein also interacts in the nucleus with β-catenin, a central regulator of gene transcription. Together these data suggest that the cleavage products of COX-2 can affect cell proliferation by mechanisms that are independent of prostaglandin synthesis.

Original languageEnglish
Article number3195
JournalInternational Journal of Molecular Sciences
Issue number9
StatePublished - 1 May 2020
Externally publishedYes


  • Cleavage
  • Cyclooxygenase-2 (COX-2)
  • Proliferation
  • Proteolysis
  • β-catenin
  • Immunoprecipitation
  • Humans
  • Immunoblotting
  • Mice, Transgenic
  • Cyclooxygenase 2/genetics
  • Tandem Mass Spectrometry
  • Animals
  • HEK293 Cells
  • Chromatography, Liquid
  • Cell Proliferation/genetics
  • Mice
  • Gene Expression Regulation, Neoplastic/genetics

ASJC Scopus subject areas

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry


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