Increased K-ras protein and activity in mouse and human lung epithelial cells at confluence

Author:

Kammouni, W.

Ramakrishna, G.

Sithanandam, G.

Smith, G. T.

Fornwald, L. W.

Masuda, A.

Takahashi, T.

Anderson, L. M.
Author Address

Natl Canc Inst Frederick, Lab Comparat Carcinogenesis, Bldg 538,Rm 205B, Ft Detrick, MD 21702 USA Natl Canc Inst Frederick, Lab Comparat Carcinogenesis, Ft Detrick, MD 21702 USA SAIC Frederick Inc, Ft Detrick, MD 21702 USA Aichi Canc Ctr, Res Inst, Div Mol Oncol, Nagoya, Aichi 4648681, Japan Anderson LM Natl Canc Inst Frederick, Lab Comparat Carcinogenesis, Bldg 538,Rm 205B, Ft Detrick, MD 21702 USA

Abstract:

Although K-ras is frequently mutated in lung adenocarcinomas, the normal function of K-ras p21 in lung is not known. In two mouse (E10 and C10) and one human (HPL1D) immortalized lung cell lines from peripheral epithelium, we have measured total K-ras p21 and active K-ras p21-GTP during cell proliferation and at growth arrest caused by confluence. In all three cell types, total K-ras p21 increased 2- to 4-fold at confluence, and active K-ras p21-GTP increased 10- to 200-fold. It was estimated that 0.03% of total K-ras p21 was in the active GTP- bound state at 50% confluence, compared with 1.4% at postconfluence. By contrast, stimulation of proliferation by serum-containing medium did not involve K-ras p21 activation, even though a rapid, marked activation of both Erk1/2 and Akt occurred. At confluence, large increases, up to 14-fold, were seen in Grb2/Sos1 complexes, which may activate K-ras p21. In sum, increased protein expression and activity of K-ras p21 are associated with growth arrest, not with proliferation, in mouse and human lung cell lines.

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