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Brain Tumor Pathology

, Volume 18, Issue 2, pp 73–81 | Cite as

Phenotypic changes associated with exogenous expression of p16INK4a in human glioma cells

  • Akio Noguchi
  • Nobuyuki Ito
  • Hiroki Sawa
  • Motoo Nagane
  • Mitsuhiro Hara
  • Isamu Saito
Original Article

Abstract

The tumor suppressorp16/CDKN2A/INK4a gene is frequently mutated, mostly by homozygous deletions in high-grade gliomas. Although the p16 protein suppresses cell proliferation primarily through inhibition of cell-cycle progression at the G1 phase, other phenotypic changes in glioma cells associated with p16INK4a alterations have not been fully described. To determine the roles of p16 alterations in glioma formation, we have established ecdysonedriven inducible p16 expression in the human glioblastoma cell line CL-4, which were derived from p16-null U87MG cells. Here we show that exogenous p16 expression in CL-4 cells results in morphological changes, with large and flattened cytoplasm, which are associated with increased formation of cytoplasmic actin-stress fibers and vinculin accumulation in the focal adhesion contacts. Adhesion of CL-4 cells to extracellular matrix proteins, such as laminin, fibronectin, and type IV collagen, significantly increased upon exogenous p16 expression, which correlated with increased expression of integrin α5 and αv. Expression of a small GTP-binding protein, Rac, also decreased. Following epidermal growth factor stimulation, phosphorylation of MAP kinases ERK1 and 2 and induction of an early immediate gene product, c-Fos, were significantly reduced in CL-4 cells with p16 expression. These results suggest that the tumor suppressor p16 may exert its antitumor effects through modulation of multiple aspects of glioblastoma phenotypes, including proliferation, invasiveness, and responsiveness to extracellular growth stimuli.

Key words

p16 Glioma Integrin Rac Adhesion Growth factor 

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Copyright information

© The Japan Society of Brain Tumor Pathology 2001

Authors and Affiliations

  • Akio Noguchi
    • 1
  • Nobuyuki Ito
    • 1
  • Hiroki Sawa
    • 1
    • 2
  • Motoo Nagane
    • 1
  • Mitsuhiro Hara
    • 3
  • Isamu Saito
    • 1
  1. 1.Department of NeurosurgeryKyorin University School of MedicineTokyoJapan
  2. 2.Hokuto Hospital, ObihiroHokkaidoJapan
  3. 3.Department of NeurosurgeryOsaka Municipal UniversityOsakaJapan

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