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Inhibition of transforming growth factor-beta signaling in normal lung epithelial cells confers resistance to ionizing radiation.

ABSTRACT: To address the functional role of radiation-induced transforming growth factor-beta (TGF-beta) signaling in a normal epithelial background, we selected a spontaneously immortalized lung epithelial cell line derived from the normal lung tissue of a dominant-negative mutant of the TGF-beta RII (DeltaRII) transgenic mouse that conditionally expressed DeltaRII under the control of the metallothionein promoter (MT-1), and assessed this cell line's response to radiation.A spontaneously immortalized lung epithelial cell culture (SILECC) was established and all analyses were performed within 50 passages. Colony-forming and terminal transferase dUPT nick end labeling (TUNEL) assays were used to assess clonogenic inhibition and apoptosis, respectively. Western-blot analysis was performed to assess the kinetics of p21, bax, and RII proteins. Transforming growth factor-beta-responsive promoter activity was measured using dual-luciferase reporter assay.Exposure to ZnSO(4) inhibited TGF-beta signaling induced either by recombinant TGF-beta1 or ionizing radiation. The SILECC, treated with either ZnSO(4) or neutralizing antibody against TGF-beta, showed a significant increase in radio-resistance compared to untreated cells. Furthermore, the expression of DeltaRII inhibited the radiation-induced up-regulation of the TGF-beta effector gene p21(waf1/cip1).Our findings imply that inhibition of radiation-induced TGF-beta signaling via abrogation of the RII function enhances the radio-resistance of normal lung epithelial cells, and this can be directly attributed to the loss of TGF-beta signaling function.

SUBMITTER: Reeves A

PROVIDER: S-EPMC1948025 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Inhibition of transforming growth factor-beta signaling in normal lung epithelial cells confers resistance to ionizing radiation.

Reeves Anna A Zagurovskaya Marianna M Gupta Seema S Shareef Mohammed M MM Mohiuddin Mohammed M Ahmed Mansoor M MM

International journal of radiation oncology, biology, physics 20070501 1

<h4>Purpose</h4>To address the functional role of radiation-induced transforming growth factor-beta (TGF-beta) signaling in a normal epithelial background, we selected a spontaneously immortalized lung epithelial cell line derived from the normal lung tissue of a dominant-negative mutant of the TGF-beta RII (DeltaRII) transgenic mouse that conditionally expressed DeltaRII under the control of the metallothionein promoter (MT-1), and assessed this cell line's response to radiation.<h4>Methods and ...[more]

PMID: 17448872

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Inhibition of transforming growth factor-beta signaling in normal lung epithelial cells confers resistance to ionizing radiation.

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Inhibition of transforming growth factor-beta signaling in normal lung epithelial cells confers resistance to ionizing radiation.

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