Tumorigenesis: It's a knockout!

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Knocking out the p53 homolog TAp73 has revealed a role for the protein in tumor suppression and the maintenance of genomic integrity.

Advocates of a tumour-suppressive function for the p53 homologue TAp73 breathed a collective sigh of relief following the recent analysis of a TAp73-specific knockout mouse.


CORBIS

Efforts to dissect the role of this protein in cancer have been hampered by the fact that the Trp73 locus actually encodes several protein products that can be divided into two groups: the transcriptionally active 'p53-like' isoforms (collectively referred to as TAp73) and their dominant-negative nemeses, the oncogenic amino-deleted proteins (collectively referred to as Delta Np73). Much to the frustration of the TAp73 community, demonstrating that these isoforms had anything more in common with p53 than sequence homology proved troublesome: the TP73 gene is rarely mutated in cancer and Trp73-knockout mice, in which both groups of isoforms are absent, are not tumour-prone. Many argued that the lack of tumour development in these animals was due to the concomitant obliteration of Delta Np73, but the lack of isoform-specific knockouts precluded any meaningful resolution.

However, a recent study published in Genes and Development by Tomasini and colleagues shows a bona fide tumour-suppressive role for TAp73. The generation (by obliteration of exons 2 and 3) of TAp73-specific null mice demonstrated that 73% developed tumours compared with only 6% of their wild-type littermates. Moreover, the loss of TAp73 resulted in a significantly shorter latency period for the development of colon, liver, intestine and stomach tumours induced by peritoneal injection of the carcinogen DMBA, indicating that TAp73 alone can act to block oncogenic transformation.

How does TAp73 exert its tumour suppressive function? Interestingly, the infertility of the TAp73-deficient cohort provided a clue to a putative mechanism. Oocytes from these animals displayed striking spindle abnormalities, indicative of a role for TAp73 in maintaining genomic stability. In agreement with this hypothesis, TAp73-deficient mouse embryonic fibroblasts (MEFs) treated with the mitosis inhibitor nocodazole failed to arrest in the G2/M phase of the cell cycle and entered inappropriate mitosis. Furthermore, prolonged nocodazole treatment resulted in the emergence of an 8N population in TAp73-deficient cells that was not observed in controls. Crucially, subsequent studies showed that these effects were tissue-specific, as lung tissue was particularly prone to aneuploidy following TAp73 loss compared with thymic tissue — a telling observation given the high frequency of lung tumours in TAp73-null mice.

This study asserts that the influence of TAp73 extends beyond tumorigenesis into the maintenance of genomic integrity, with repercussions for the fields of both cancer and infertility. The question of whether TAp73 is a tumour suppressor might be put to rest for now, but new questions emerge: is TAp73 affecting the spindle assembly complex? Does it regulate the cell cycle or mitotic fuse proteins? Moreover, these data have further implications for the ongoing debate regarding the links between genetic instability, aneuploidy and cancer. Perhaps TAp73 is one of those proteins that will continue to court controversy.

Safia Ali Danovi

References

Tomasini, R. et al. TAp73 knockout shows genomic instability with infertility and tumor supressor functions. Genes Dev. 22, 2677–2691 (2008) | Article | PubMed |
Melino, G. et al. p73: Friend or foe in tumorigenesis? Nature Rev. Cancer 2, 605–615 (2002) | Article | PubMed |