Abstract
The p53 tumor suppressor protein plays an important role in preventing cancer development by arresting or killing potential tumor cells. Downregulated p53 levels, or mutations within the p53 gene, leading to the loss of p53 activity, are found in many breast carcinomas. Here we demonstrate that the p53 gene is transcriptionally upregulated in the normal mouse mammary gland at midpregnancy. We show that the specific isoform nuclear factor 1-C2 (NF1-C2) plays an important role in this activation. Functional mutation of the NF1-binding site in the mouse p53 promoter resulted in a reduction of the gene expression to less than 30% in mammary epithelial cells. By the use of two powerful techniques, chromatin immunoprecipitation and oligonucleotide decoy, we verify the importance of NF1-C2 in p53 gene activation in vivo. These findings demonstrate a broader role for NF1-C2 in the mammary gland at midpregnancy, beyond its earlier reported activation of milk protein genes. We also demonstrate that NF1-A1 proteins are produced in the mouse mammary gland. However, due to their lower affinity to the NF1-binding site, these proteins are not involved in the transcriptional upregulation of p53 at midpregnancy. This paper constitutes the first report demonstrating the importance of NF1 proteins in the p53 gene activation in the mouse mammary gland. It is also the first time that p53 gene activation is coupled to a specific, endogenously expressed NF1 isoform.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Almog N and Rotter V . (1997). Biochim. Biophys. Acta, 1333, F1–F27.
Andres AC, van der Valk MA, Schonenberger CA, Fluckiger F, LeMeur M, Gerlinger P and Groner B . (1988). Genes Dev., 2, 1486–1495.
Ausubel F, Brent R, Moore D, Smith J, Seidman J and Struhl K . (1987). Current Protocols in Molecular Biology, Wiley Interscience: New York, pp. 12.1.1–12.1.4.
Balint E and Reisman D . (1996). Cancer Res., 56, 1648–1653.
Banerjee D, Lenz HJ, Schnieders B, Manno DJ, Ju JF, Spears CP, Hochhauser D, Danenberg K, Danenberg P and Bertino JR . (1995). Cell Growth Differ., 6, 1405–1413.
Bengtsson SH, Madeyski-Bengtson K, Nilsson J and Bjursell G . (2002). Biochem. J., 365, 481–488.
Bienz-Tadmor B, Zakut-Houri R, Libresco S, Givol D and Oren M . (1985). EMBO J., 4, 3209–3213.
Bradford MM . (1976). Anal. Biochem., 72, 248–254.
Chylicki K, Ehinger M, Svedberg H, Bergh G, Olsson I and Gullberg U . (2000). Cell Growth Differ., 11, 315–324.
Coles C, Condie A, Chetty U, Steel CM, Evans HJ and Prosser J . (1992). Cancer Res., 52, 5291–5298.
Ehinger M, Nilsson E, Persson AM, Olsson I and Gullberg U . (1995). Cell Growth Differ., 6, 9–17.
Feinstein E, Gale RP, Reed J and Canaani E . (1992). Oncogene, 7, 1853–1857.
Furlong EE, Rein T and Martin F . (1996). Mol. Cell Biol., 16, 5933–5945.
Goyal N, Knox J and Gronostajski RM . (1990). Mol. Cell Biol., 10, 1041–1048.
Gronostajski RM . (2000). Gene, 249, 31–45.
Hale TK, Myers C, Maitra R, Kolzau T, Nishizawa M and Braithwaite AW . (2000). J. Biol. Chem., 275, 17991–17999.
Hellin AC, Calmant P, Gielen J, Bours V and Merville MP . (1998). Oncogene, 16, 1187–1195.
Kane R, Finlay D, Lamb T and Martin F . (2000). Adv. Exp. Med. Biol., 480, 117–122.
Kannius-Janson M, Johansson EM, Bjursell G and Nilsson J . (2002). J. Biol. Chem., 277, 17589–17596.
Kannius-Janson M, Lidberg U, Hulten K, Gritli-Linde A, Bjursell G and Nilsson J . (1998). Biochem. J., 336, 577–585.
Kirch HC, Flaswinkel S, Rumpf H, Brockmann D and Esche H . (1999). Oncogene, 18, 2728–2738.
Kruse U and Sippel AE . (1994). FEBS Lett., 348, 46–50.
Kuperwasser C, Pinkas J, Hurlbut GD, Naber SP and Jerry DJ . (2000). Cancer Res., 60, 2723–2729.
Lang D, Miknyoczki SJ, Huang L and Ruggeri BA . (1998). Oncogene, 16, 1593–1602.
Lidberg U, Kannius-Janson M, Nilsson J and Bjursell G . (1998). J. Biol. Chem., 273, 31417–31426.
Lidberg U, Nilsson J, Stromberg K, Stenman G, Sahlin P, Enerback S and Bjursell G . (1992). Genomics, 13, 630–640.
Morishita R, Gibbons GH, Horiuchi M, Ellison KE, Nakama M, Zhang L, Kaneda Y, Ogihara T and Dzau VJ . (1995). Proc. Natl. Acad. Sci. USA, 92, 5855–5859.
Morishita R, Sugimoto T, Aoki M, Kida I, Tomita N, Moriguchi A, Maeda K, Sawa Y, Kaneda Y, Higaki J and Ogihara T . (1997). Nat. Med., 3, 894–899.
Mukhopadhyay SS, Wyszomierski SL, Gronostajski RM and Rosen JM . (2001). Mol. Cell Biol., 21, 6859–6869.
Nayak BK and Das BR . (1999). Mol. Biol. Rep., 26, 223–230.
Nebl G, Mermod N and Cato AC . (1994). J. Biol. Chem., 269, 7371–7378.
Oren M . (1999). J. Biol. Chem., 274, 36031–36034.
Osada S, Matsubara T, Daimon S, Terazu Y, Xu M, Nishihara T and Imagawa M . (1999). Biochem. J., 342, 189–198.
Rafty LA, Santiago FS and Khachigian LM . (2002). EMBO J., 21, 334–343.
Raman V, Martensen SA, Reisman D, Evron E, Odenwald WF, Jaffee E, Marks J and Sukumar S . (2000). Nature, 405, 974–978.
Saifudeen Z, Dipp S and El-Dahr SS . (2002). J. Clin. Invest., 109, 1021–1030.
Shaulsky G, Goldfinger N, Peled A and Rotter V . (1991). Cell Growth Differ., 2, 661–667.
Sivaraman L, Conneely OM, Medina D and O’Malley BW . (2001). Proc. Natl. Acad. Sci. USA, 98, 12379–12384.
Soddu S, Blandino G, Scardigli R, Coen S, Marchetti A, Rizzo MG, Bossi G, Cimino L, Crescenzi M and Sacchi A . (1996). J. Cell Biol., 134, 193–204.
Soini Y, Kamel D, Nuorva K, Lane DP, Vahakangas K and Paakko P . (1992). Virchows Arch. A – Pathol. Anat. Histopathol., 421, 415–420.
Strange R, Li F, Saurer S, Burkhardt A and Friis RR . (1992). Development, 115, 49–58.
Stromqvist M, Hernell O, Hansson L, Lindgren K, Skytt A, Lundberg L, Lidmer AS and Blackberg L . (1997). Arch. Biochem. Biophys., 347, 30–36.
Sun X, Shimizu H and Yamamoto K . (1995). Mol. Cell Biol., 15, 4489–4496.
Wiseman BS and Werb Z . (2002). Science, 296, 1046–1049.
Yang BS, Gilbert JD and Freytag SO . (1993). Mol. Cell Biol., 13, 3093–3102.
Acknowledgements
We are grateful to Kerstin Dahlenborg for technical assistance and Ola Brusehed for help with mammary gland preparations. We also thank Dr N Tanese, NYU Medical center, NY, for the NF1-C specific antibody and Dr RM Gronostajski, Lerner Institute, OH, for the pCHNF1 expression plasmids. This work was supported by grants from the Swedish Medical Reasearch Council, Assar Gabrielsson foundation, Fredrik and Ingrid Thuring foundation, and Magnus Bergvall foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Johansson, E., Kannius-Janson, M., Bjursell, G. et al. The p53 tumor suppressor gene is regulated in vivo by nuclear factor 1-C2 in the mouse mammary gland during pregnancy. Oncogene 22, 6061–6070 (2003). https://doi.org/10.1038/sj.onc.1206884
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206884
Keywords
This article is cited by
-
NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation
Nature Communications (2023)
-
Nuclear factor I-C disrupts cellular homeostasis between autophagy and apoptosis via miR-200b-Ambra1 in neural tube defects
Cell Death & Disease (2021)
-
Polymorphisms in 5′ proximal regulating region of THRSP gene are associated with fat production in pigs
3 Biotech (2020)
-
Aryl hydrocarbon receptor gene transitions (c.-742C>T; c.1661G>A) and idiopathic male infertility: a case-control study with in silico and meta-analysis
Environmental Science and Pollution Research (2017)
-
Forkhead Box F1 promotes breast cancer cell migration by upregulating lysyl oxidase and suppressing Smad2/3 signaling
BMC Cancer (2016)
