PKM2 uses control of HuR localization to regulate p27 and cell cycle progression in human glioblastoma cells

Joydeep Mukherjee, Shigeo Oba, Wendy L. See, Joanna J. Phillips, Annette M. Molinaro, Russell O. Pieper

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The M2 isoform of pyruvate kinase (PK) is upregulated in most cancers including glioblastoma. Although PKM2 has been reported to use dual kinase activities to regulate cell growth, it also interacts with phosphotyrosine (pY)-containing peptides independently of its kinase activity. The potential for PKM2 to use the binding of pY-containing proteins to control tumor growth has not been fully examined. We here describe a novel mechanism by which PKM2 interacts in the nucleus with the RNA binding protein HuR to regulate HuR sub-cellular localization, p27 levels, cell cycle progression and glioma cell growth. Suppression of PKM2 in U87, T98G and LN319 glioma cells resulted in increased p27 levels, defects in entry into mitosis, increased centrosome number, and decreased cell growth. These effects could be reversed by shRNA targeting p27. The increased levels of p27 in PKM2 knock-down cells were caused by a loss of the nuclear interaction between PKM2 and HuR, and a subsequent cytoplasmic re-distribution of HuR, which in turn led to increased cap-independent p27 mRNA translation. Consistent with these results, the alterations in p27 mRNA translation, cell cycle progression and cell growth caused by PKM2 suppression could be reversed in vitro and in vivo by suppression of HuR or p27 levels, or by introduction of forms of PKM2 that could bind pY, regardless of their kinase activity. These results define a novel mechanism by which PKM2 regulates glioma cell growth, and also define a novel set of potential therapeutic targets along the PKM2-HuR-p27 pathway.

Original languageEnglish
Pages (from-to)99-111
Number of pages13
JournalInternational Journal of Cancer
Volume139
Issue number1
DOIs
Publication statusPublished - 01-07-2016

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Glioblastoma
Cell Cycle
Phosphotyrosine
Glioma
Growth
Phosphotransferases
Protein Biosynthesis
Centrosome
Pyruvate Kinase
RNA-Binding Proteins
Mitosis
Small Interfering RNA
Neoplasms
Protein Isoforms
Cell Proliferation
Peptides
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Mukherjee, Joydeep ; Oba, Shigeo ; See, Wendy L. ; Phillips, Joanna J. ; Molinaro, Annette M. ; Pieper, Russell O. / PKM2 uses control of HuR localization to regulate p27 and cell cycle progression in human glioblastoma cells. In: International Journal of Cancer. 2016 ; Vol. 139, No. 1. pp. 99-111.
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PKM2 uses control of HuR localization to regulate p27 and cell cycle progression in human glioblastoma cells. / Mukherjee, Joydeep; Oba, Shigeo; See, Wendy L.; Phillips, Joanna J.; Molinaro, Annette M.; Pieper, Russell O.

In: International Journal of Cancer, Vol. 139, No. 1, 01.07.2016, p. 99-111.

Research output: Contribution to journalArticle

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