• Myc
• p53
• tumor suppression

Activated oncogenes direct cells toward uncontrolled proliferation, but
concomitantly elicit tumor suppressive responses, such as apoptosis or
senescence, that must be bypassed in order to allow tumor progression.
Oncogenes like RAS, for instance, generally induce senescence, while
oncogenes like Myc, generally induce apoptosis. Even though apoptotic
mechanisms have been widely uncovered during this decade; and their
fundamental contribution to tumor suppression is widely accepted, how this
phenomenon is linked to oncogene overexpression remains to be fully
understood.
Myc induced apoptosis is a biological response requiring an active form of 53
protein for its correct establishment. P53 is accumulated in response to a wide
variety of stress signals and, according to cell type, context and damaging
stimulus, can induce three different transcriptional programs: senescence, cell
cycle arrest and apoptosis. Remarkably, in conditions of Myc ectopic expression,
p53 is committed to establish its apoptotic program.
My Thesis investigation consist on a screening, using “gene candidate
approach” for genes involved in the establishment of the p53 apoptotic program
upon Myc ectopic expression. The main criteria used for the selection of the
genes was their ability to regulate p53 function in a way so as to influence its
decision to induce apoptosis or cell cycle arrest. Accordingly, the genes chosen as
a focus of the investigation are: the methyltransferase SET7/9, and the
homeodomain interacting protein kinase 2 (HIPK2).
The idea of SET7/9 as a possible candidate for the regulation of Myc induced
apoptosis came soon after the publication of the paper of J. Kurash (Kurash et al.
2008). In this paper, it was demonstrated how methylation of p53 LYS369,
performed by SET7/9, is required in order to establish a cell cycle arrest or
apoptosis in response to DNA damage. For instance, SET7/9 null MEFs were
unable to arrest the cell cycle following treatment with adryamicin, a DNA
damage inducing agent. This lack of cell cycle arrest correlate with p53 failure to
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induce downstream targets required for its cell cycle arrest program such as p21
and PUMA.
HIPK2 was shown to phosphorylate p53 SER46 upon severe, nonreparable
DNA damage, this kind of phosphorylation is considered a point of no return. p53
phosphorylated in this way shifts its transcriptional program from cell cycle arrest
to apoptosis, thereby inducing the dead of cells carrying an excessive amount of
DNA damage that is too high to be repaired. HIPK2 lacking cells for instance,
show a significant decrease in apoptosis following adryamicin induced DNA
damage.
These proteins thus, are crucial in regulating p53 function in response to
genotoxic insults, but however, this role has been investigated only in response to
genotoxic stress induced by UV irradiation or adryamicin, and little is known
about whether they are able to regulate p53 in response to oncogenic stress, such
as in conditions of Myc overexpression.