Abstract
Neoplasia is characterized by cells' loss of self-control due to
deregulated apoptotic and cell proliferation pathways. Anticancer
treatments aim to induce either cell cycle arrest or apoptosis, and these
effects are in most part mediated by proteins, like p53 and p73, which
are involved in and able to mediate both processes. P53 is the gene found
most mutated in tumors and consequently its pivotal role in the
regulation of cell cycle and apoptosis is impaired.
The P53 homologue P73,
on the other hand, is .rarely mutated in human tumors The P73 gene gives
rise to many different protein isoforms, including the transcriptionally
active p73 isoforms (TAp73) and the deltaNp73 isoforms, the latter
lacking the amino-terminal transactivation (TA) domain. TAp73 isoforms
are regarded most similar to p53 and to act as tumor suppressors, whereas
the deltaNp73 isoforms acts more like oncogenes, preventing p53 and TAp73
from exerting their functions. Nevertheless, TAp73 isoforms are found
overexpressed and to, contribute to cellular chemoresistance in some
tumors. We have shown that the TAp73alpha isoform can prevent
drug-induced apoptosis in small cell lung carcinoma cells and that this
effect is exerted upstream of the mitochondria. In addition, we have
characterized the domains within the protein needed for the pro- or
anti-apoptotic effect of p73. Furthermore, in the carboxy-terminal region
of p73 we characterized a TA domain containing a putative PKC
phosporylation site. The characterized TA domain was active on promoters
of cell cycle regulatory genes, and its activity was found to be
regulated by phosphorylation.
In conclusion, these studies provide a better understanding into the
structure-function properties of p73 and how different domains can
selectively affect and regulate cell cycle progression and/or apoptosis.
