Fusion proteins of retinoid receptors antagonize TGF-beta-induced growth inhibition of lung epithelial cells.
Transforming growth factor-beta1 (TGF-beta) is a growth factor that has multiple functions including potent inhibition of cell growth. TGF-beta signals by binding to its cell surface serine/threonine kinase receptors, which in turn phosphorylate downstream signal transducers, Smad2 and Smad3. Phosphorylated Smad2 and Smad3, together with Smad4, enter the nucleus and associate with various transcription factors. This complex of transcription factors regulates transcription of a diverse group of genes, leading to growth arrest at G1 phase. Through a functional expression cloning approach, a gag-retinoid X receptor beta (gag-RXRbeta) fusion protein was found to antagonize TGF-beta-induced growth inhibition of mink lung epithelial cells and the fusion between gag and RXRbeta is essential for resistance to the growth inhibition. Like gag-RXRbeta, the oncogenic PLZF-RARalpha fusion protein also antagonizes TGF-beta-induced growth inhibition, and the fusion between PLZF and RARalpha is essential for resistance to TGF-beta. Moreover, TGF-beta and retinoic acid (RA) cooperatively induce growth inhibition as well as transcription of the p15(ink4b) gene, while PLZF-RARalpha represses TGF-beta-induced expression of the p15(ink4b) gene. Together, these results suggest that the TGF-beta and RA pathways cooperate to inhibit cell growth and that PLZF-RARalpha -mediated resistance to TGF-beta may facilitate the development of the PLZF-RARalpha-induced leukemia.
La
Ping
P
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Pittsburgh 19104-6160, USA.
Morgan
Trish A
TA
Sykes
Stephen M
SM
Mao
Hua
H
Schnepp
Robert W
RW
Petersen
Clark D
CD
Hua
Xianxin
X
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003001:Cloning, Molecular; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015683:Gene Products, gag / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology*; D008907:Mink; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D015683:Gene Products, gag; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C118318:PLZF-RARalpha fusion protein, human; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D014212:Tretinoin