Abstract
TP53INP1 is an alternatively spliced gene encoding two nuclear protein isoforms (TP53INP1α and TP53INP1β), whose transcription is activated by p53. When overexpressed, both isoforms induce cell cycle arrest in G1 and enhance p53-mediated apoptosis. TP53INP1s also interact with the p53 gene and regulate p53 transcriptional activity. We report here that TP53INP1 expression is induced during experimental acute pancreatitis in p53−/− mice and in cisplatin-treated p53−/− mouse embryo fibroblasts (MEFs). We demonstrate that ectopic expression of p73, a p53 homologue, leads to TP53INP1 induction in p53-deficient cells. In turn, TP53INP1s alters the transactivation capacity of p73 on several p53-target genes, including TP53INP1 itself, demonstrating a functional association between p73 and TP53INP1s. Also, when overexpressed in p53-deficient cells, TP53INP1s inhibit cell growth and promote cell death as assessed by cell cycle analysis and colony formation assays. Finally, we show that TP53INP1s potentiate the capacity of p73 to inhibit cell growth, that effect being prevented when the p53 mutant R175H is expressed or when p73 expression is blocked by a siRNA. These results suggest that TP53INP1s are functionally associated with p73 to regulate cell cycle progression and apoptosis, independently from p53.
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
Barak Y, Juven T, Haffner R and Oren M . (1993). EMBO J., 12, 461–468.
Chau BN, Chen TT, Wan YY, DeGregori J and Wang JY . (2004). Mol. Cell. Biol., 24, 4438–4447.
Chirgwin JM, Przybyla AE, MacDonald RJ and Rutter WJ . (1979). Biochemistry, 18, 5294–5299.
Courtois S, de Fromentel CC and Hainaut P . (2004). Oncogene, 23, 631–638.
Das S, El-Deiry WS and Somasundaram K . (2003a). Oncogene, 22, 8394–8402.
Das S, El-Deiry WS and Somasundaram K . (2003b). J. Biol. Chem., 278, 18313–18320.
Di Como CJ, Gaiddon C and Prives C . (1999). Mol. Cell. Biol., 19, 1438–1449.
Dusetti NJ, Tomasini R, Azizi A, Barthet M, Vaccaro MI, Fiedler F, Dagorn JC and Iovanna JL . (2000). Biochem. Biophys. Res. Commun., 277, 660–667.
el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler K and Vogelstein B . (1993). Cell, 75, 817–825.
Flores ER, Tsai KY, Crowley D, Sengupta S, Yang A, McKeon F and Jacks T . (2002). Nature, 416, 560–564.
Fontemaggi G, Gurtner A, Strano S, Higashi Y, Sacchi A, Piaggio G and Blandino G . (2001). Mol. Cell. Biol., 21, 8461–8470.
Fontemaggi G, Kela I, Amariglio N, Rechavi G, Krishnamurthy J, Strano S, Sacchi A, Givol D and Blandino G . (2002). J. Biol. Chem., 277, 43359–43368.
Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin Jr WG, Levrero M and Wang JY . (1999). Nature, 399, 806–809.
Hamer G, Gademan IS, Kal HB and de Rooij DG . (2001). Oncogene, 20, 4298–4304.
Ikawa S, Nakagawara A and Ikawa Y . (1999). Cell Death Differ., 6, 1154–1161.
Iovanna J, Orelle B, Keim V and Dagorn JC . (1991). J. Biol. Chem., 266, 24664–24669.
Irwin MS and Kaelin WG . (2001). Cell Growth Differ., 12, 337–349.
Ishida S, Yamashita T, Nakaya U and Tokino T . (2000). Jpn. J. Cancer Res., 91, 174–180.
Jost CA, Marin MC and Kaelin Jr WG . (1997). Nature, 389, 191–194.
Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lelias JM, Dumont X, Ferrara P, McKeon F and Caput D . (1997). Cell, 90, 809–819.
Miyashita T and Reed JC . (1995). Cell, 80, 293–299.
Niederau C, Ferrell LD and Grendell JH . (1985). Gastroenterology, 88, 1192–1204.
Obad S, Brunnstrom H, Vallon-Christersson J, Borg A, Drott K and Gullberg U . (2004). Oncogene, 23, 4050–4059.
Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya Y, Monden M and Nakamura Y . (2001). Mol. Cell., 8, 85–94.
Oniscu A, Sphyris N, Morris RG, Bader S and Harrison DJ . (2004). J. Clin. Pathol., 57, 492–498.
Rodicker F and Putzer BM . (2003). Cancer Res., 63, 2737–2741.
Sablina AA, Chumakov PM and Kopnin BP . (2003). J. Biol. Chem., 278, 27362–27371.
Shimodaira H, Yoshioka-Yamashita A, Kolodner RD and Wang JY . (2003). Proc. Natl. Acad. Sci. USA, 100, 2420–2425.
Shinbo J, Ozaki T, Nakagawa T, Watanabe K, Nakamura Y, Yamazaki M, Moriya H, Nakagawara A and Sakiyama S . (2002). Biochem. Biophys. Res. Commun., 295, 501–507.
Stiewe T and Pützer B . (2001). Apoptosis, 6, 447–452.
Strano S, Rossi M, Fontemaggi G, Munarriz E, Soddu S, Sacchi A and Blandino G . (2001). FEBS Lett., 490, 163–170.
Strano S, Munarriz E, Rossi M, Cristofanelli B, Shaul Y, Castagnoli L, Levine AJ, Sacchi A, Cesareni G, Oren M and Blandino G . (2000). J. Biol. Chem., 275, 29503–29512.
Tomasini R, Samir AA, Carrier A, Isnardon D, Cecchinelli B, Soddu S, Malissen B, Dagorn JC, Iovanna JL and Dusetti NJ . (2003). J. Biol. Chem., 278, 37722–37729.
Tomasini R, Samir AA, Pebusque MJ, Calvo EL, Totaro S, Dagorn JC, Dusetti NJ and Iovanna JL . (2002). Eur. J. Cell Biol., 81, 294–301.
Tomasini R, Samir AA, Vaccaro MI, Pebusque MJ, Dagorn JC, Iovanna JL and Dusetti NJ . (2001). J. Biol. Chem., 276, 44185–44192.
Torigoe T, Izumi H, Ishiguchi H, Yoshida Y, Tanabe M, Yoshida T, Igarashi T, Niina I, Wakasugi T, Imaizumi T, Momii Y, Kuwano M and Kohno K . (2005). Curr. Med. Chem. Anti-Canccer Agents, 5, 15–27.
Tsuji K, Mizumoto K, Yamochi T, Nishimoto I and Matsuoka M . (2002). J. Biol. Chem., 277, 2951–2957.
Tullo A, Mastropasqua G, Bourdon JC, Centonce P, Gostissa M, Costanzo A, Levrero M, Del Sal G, Saccone C and Sbisà E . (2003). Oncogene, 22, 8738–8748.
Yang A, Kaghad M, Caput D and McKeon F . (2002). Trends Genet., 18, 90–95.
Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J, Vagner C, Bonnet H, Dikkes P, Sharpe A, McKeon F and Caput D . (2000). Nature, 404, 99–103.
Acknowledgements
We thank Drs S Vasseur and P Soubeyran for helpful comments, V Fontaine for her help in Western blots and monoclonal antibody characterizations, A Giovannetti for siRNA and FACS analysis, R Grimaud and P Berthézène for technical help. We are grateful to G Blandino and S Das for providing us with expression plasmids (pcDNA-p73α-HA and pcDNA-p53R175H) and adenovirus (Ad-p73β), respectively. This work was supported by grants from INSERM R Tomasini is supported by a fellowship from the Ministère de la Recherche et de la Technologie, and J Nowak is supported by a fellowship from the Région Provence-Alpes-Côte-d’Azur and INSERM.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tomasini, R., Seux, M., Nowak, J. et al. TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activity. Oncogene 24, 8093–8104 (2005). https://doi.org/10.1038/sj.onc.1208951
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208951
Keywords
This article is cited by
-
Dual inhibition of EZH1/2 induces cell cycle arrest of B cell acute lymphoblastic leukemia cells through upregulation of CDKN1C and TP53INP1
International Journal of Hematology (2023)
-
Inhibition of Rac1 attenuates radiation-induced lung injury while suppresses lung tumor in mice
Cell Death Discovery (2022)
-
Circulating microRNAs as biomarkers of environmental exposure to polycyclic aromatic hydrocarbons: potential and prospects
Environmental Science and Pollution Research (2021)
-
RNA-binding protein MSI2 isoforms expression and regulation in progression of triple-negative breast cancer
Journal of Experimental & Clinical Cancer Research (2020)
-
MicroRNA-200a confers chemoresistance by antagonizing TP53INP1 and YAP1 in human breast cancer
BMC Cancer (2018)