Inactivation of TGF-beta signaling in lung cancer results in increased CDK4 activity that can be rescued by ELF.
Escape from TGF-beta inhibition of proliferation is a hallmark of multiple cancers including lung cancer. We explored the role of ELF, crucial TGF-beta adaptor protein identified from endodermal progenitor cells, in lung carcinogenesis and cell-cycle regulation. Interestingly, elf-/- mice develop multiple defects that include lung, liver, and cardiac abnormalities. Four out of 6 lung cancer and mesothelioma cell lines displayed deficiency of ELF expression with increased CDK4 expression. Immunohistochemistry and Western blot analysis of primary human lung cancers also showed decreased ELF expression and overexpression of CDK4. Moreover, rescue of ELF in ELF-deficient cell lines decreased the expression of CDK4 and resulted in accumulation of G1/S checkpoint arrested cells. These results suggest that disruption in TGF-beta signaling mediated by loss of ELF in lung cancer leads to cell-cycle deregulation by modulating CDK4 and ELF highlights a key role of TGF-beta adaptor protein in suppressing early lung cancer.
Baek
Hye Jung
HJ
Department of Surgery, Laboratory of Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Lombardi Cancer Center, Georgetown University, Washington, DC, USA.
Kim
Sang Soo
SS
da Silva
Fabio May
FM
Volpe
Eugene A
EA
Evans
Stephen
S
Mishra
Bibhuti
B
Mishra
Lopa
L
Marshall
M Blair
MB
D000818:Animals; D002277:Carcinoma / Q000201:enzymology / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D002453:Cell Cycle; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D016193:G1 Phase / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000502:physiology*; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D013049:Spectrin
D002352:Carrier Proteins; D051358:Cyclin-Dependent Kinase 4; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; D013049:Spectrin