Abstract
The p73 locus gene has a complex structure encoding a plethora of isoforms. The different
ΔN truncated isoforms of p73 may exert different activities depending on the cellular
context. The β isoform of ΔNp73 seems to have a particular pattern of action even
if its role in cell cycle and mitosis is still under investigation. To gain further
knowledge of ΔNp73β’s function, we investigated the effects of its over-expression
in tumour cellular models, using the tetracycline-inducible expression system. In
the human lung carcinoma cell line H1299, ΔNp73β over-expression resulted in suppression
of cell growth and in cell death. Surprisingly stable over-expression of ΔNp73β impaired
the genomic stability of tumour cells, leading to the formation of tetraploid cells.
The cells become enlarged and multinucleate, with incorrect mitotic figures, and died
by apoptotic-independent pathways. Our data suggest that ΔNp73β-induced aberrant mitosis
evades the control of the mitotic spindle assay checkpoint, leading to tetraploidy
and cell death through mitotic catastrophe rather than apoptosis. The various C-terminal
regions of ΔNp73 may influence the final cellular phenotype and we assume that the
β one in particular could be important in both cell growth control and regulation
of mitosis.
Keywords
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References
- Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome.Cancer Res. 2000; 60: 6788-6793
- Surfing the p53 network.Nature. 2000; 408: 307-310
- From p63 to p53 across p73.FEBS Lett. 2001; 490: 163-170
- P53, p63 and p73 – solos, alliances and feuds among family members.Biochim Biophys Acta. 2001; 1552: 47-59
- P63 and p73: roles in development and tumor formation.Mol Cancer Res. 2004; 2: 371-386
- DeltaNp73beta is active in transactivation and growth suppression.Mol Cell Biol. 2004; 24: 487-501
- Characterization of p73 functional domains necessary for transactivation and growth suppression.Oncogene. 2003; 22: 4333-4347
- The p53 family: same response, different signals?.Mol Med Today. 1999; 5: 387-392
- The common and distinct target genes of the p53 family transcription factors.Cell Mol Life Sci. 2004; 61: 822-842
- Identification of direct p73 target genes combining DNA microarray and chromatin immunoprecipitation analyses.J Biol Chem. 2002; 277: 43359-43368
- P73 is regulated by phosphorylation at the G2/M transition.J Biol Chem. 2003; 278: 49196-49202
- A role of p73 in mitotic exit.J Biol Chem. 2005; 280: 30354-30360
- P53 induces the expression of its antagonist p73 Delta N, establishing an autoregulatory feedback loop.Oncogene. 2002; 21: 4715-4727
- Human delta Np73 regulates a dominant negative feedback loop for TAp73 and p53.Cell Death Differ. 2001; 8: 1213-1223
- ΔNp73 facilitates cell immortalization and cooperates with oncogenic Ras in cellular transformation in vivo.Mol Cell Biol. 2003; 23: 5540-5555
- Transactivation-deficient DeltaTA-p73 acts as an oncogene.Cancer Res. 2002; 62: 3598-3602
- DeltaNp73 can modulate the expression of various genes in a p53-independent fashion.Oncogene. 2003; 22: 8246-8254
- Up-regulation of NFkappaB-responsive gene expression by DeltaNp73alpha in p53 null cells.Exp Cell Res. 2006; 312: 1254-1264
- Effects of inducible overexpression of DNp73[alpha] on cancer cell growth and response to treatment in vitro and in vivo.Cell Death Differ. 2005; 12: 805-814
- Questioning the oncogenic role of DeltaNp73alpha in different cell lines expressing p53 or not.Cancer Biol Ther. 2006; 5: 794-803
- In vivo evaluation of the role of DNp73alpha protein in regulating the p53-dependent apoptotic pathway after treatment with cytotoxic drugs.Int J Cancer. 2007; 120: 506-513
- DeltaNp73: misunderstood protein?.Cancer Biol Ther. 2006; 5: 804-807
- Animal cell cycles and their control.Ann Rev Biochem. 1992; 61: 441-470
- An anti-apoptotic role for the p53 family member, p73, during developmental neuron death.Science. 2000; 289: 304-306
- TAp73/DeltaNp73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma.Cell Death Differ. 2005; 12: 1564-1577
- If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells.Drug Resist Updat. 2001; 4: 303-313
- Telomerase inhibition by siRNA causes senescence and apoptosis in Barrett’s adenocarcinoma cells: mechanism and therapeutic potential.Mol Cancer. 2005; 4: 24
- Oligonucleotide N3’ → P5’ phosphoramidates as efficient telomerase inhibitors.Oncogene. 2002; 21: 638-642
- C-terminal p73 isoforms repress transcriptional activity of the human telomerase reverse transcriptase (hTERT) promoter.J Biol Chem. 2005; 280: 40402-40405
- Regulation of telomerase activity by the p53 family member p73.Oncogene. 2006; 25: 813-826
- Mitotic catastrophe results in cell death by caspase-dependent and caspase-independent mechanisms.Cell Cycle. 2006; 5: 53-60
- Chemical induction of mitotic checkpoint override in mammalian cells results in aneuploidy following a transient tetraploid state.Mutat Res. 1996; 372: 181-194
- On the road to cancer: aneuploidy and the mitotic checkpoint.Nat Rev Cancer. 2005; 5: 773-785
Article info
Publication history
Published online: November 13, 2008
Accepted:
September 23,
2008
Received in revised form:
September 1,
2008
Received:
July 3,
2008
Identification
Copyright
© 2008 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.