The role of NFI in growth-dependent regulation of gene expression

NFI proteins are transcription factors playing a role in the regulation of expression of genes implicated in many processes like cell cycle, differentiation and growth [1]. TGF-β plays a major role in restricting proliferation of cells entering into apoptosis, senescence or terminal differentiation [2], and Smad proteins are seminal components of the TGF-β signaling pathway. To date, no role has been found for the NFI proteins in TGF-β dependent growth control processes. However, a large number of NFI target genes have been identified that are repressed by TGF-β [1].
Our studies are focused on the mechanism(s) of NFI-mediated gene expression in growth-arrested cells. Model genes included in our studies are known targets of NFI transcription factor and are also regulated by growth, senescence and cell cycle [1, 3, 4].
Our studies showed, for the first time, a direct interaction between NFI and Smad proteins in vitro and in vivo [3]. We have also shown that the formation of these protein complexes is dependent on TGF-β and p38 signaling pathways [5].
It has been recently suggested that NFI is a tumor suppressor [4]. It has been also published that cancer cells treated with TGF-β display decreased tumorigenicity and increased senescent phenotype [2]. In view of these findings it is crucial to understand the mechanism how NFI regulates gene expression by growth, cell cycle and senescence.

This project is in collaboration with Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovak Republic, principal investigator Dr. Katarina Luciakova
(http://www.exon.sav.sk/web/index.php?lang=en&nodeid=4&section=departments&department_id=6)

Literature

[1] Gronostajski, R., M. (2000): Roles of the NFI/CTF gene family in transcription and development. Gene, 249, 31-45

[2] Massagué J, Seoane J, Wotton D. (2005): Smad transcription factors. Genes Dev. 19 (23), 783-2810

[3] Luciakova, K., Kollarovic, G., Barath, P., Nelson, B. D. (2008): Growth-dependent repression of human adenine nucleotide translocator-2 (ANT2) transcription: evidence for the participation of Smad and Sp family proteins in the NF1-dependent repressor complex. Biochem J., 412, 123-30

[4] Nilsson J, Helou K, Kovács A, Bendahl PO, Bjursell G, Fernö M, Carlsson P, Kannius-Janson M. (2010): Nuclear Janus-activated kinase 2/nuclear factor 1-C2 suppresses tumorigenesis and epithelial-to-mesenchymal transition by repressing Forkhead box F1. Cancer Res. 70 (5), 2020-2029

[5] Luciakova, K., Kollarovic, G., Kretova, M., Sabova, M., Nelson, B. D. (2011): TGF-β signals the formation of a unique NF1/Smad4-dependent transcription repressor-complex in human diploid fibroblasts. Biochem. Biophys. Res. Commun. 411 (3), 648-653