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Seminario IFIBYNE-DFBMC Dr. Bruno Amati<br>
Jueves 9 de Agosto a las 13:00 horas.<br>
Italian Institute of Technology (IIT) & European Institute of
Oncology (IEO), Milan, Italy.<br><br>
Role of the prolyl-isomerase Pin1 in Myc-induced lymphomagenesis: direct
or indirect?<br>
The c-myc proto-oncogene is activated by translocation in Burkitt's
lymphoma and is frequently subject to secondary mutations. Substitutions
in codon 58, in particular, stabilize the c-Myc protein (Myc) and augment
its oncogenic potential. In wild-type Myc, phosphorylation of Ser 62
primes phosphorylation of Thr 58, providing a landing pad for the
peptidyl prolyl-isomerase Pin1, which in turn promotes Ser 62
dephosphorylation and Myc degradation. However, genetic data are missing
to address whether Pin1 influences Myc-induced lymphomagenesis. We show
here that genetic ablation of Pin1 in Eµ-myc transgenic mice starkly
reduced lymphoma onset and penetrance. In pre-malignant Pin1-deficient
B-cells, the proliferative response to Myc was selectively impaired, in
the absence of changes in either steady-state Myc levels or Ser 62
phosphorylation. Similarly, in Pin1-/- mouse embryo fibroblasts (MEFs),
prolonged Myc activation inhibited proliferation. In either B-cells or
MEFs, Myc-induced apoptosis occurred independently from Pin1. Although
Eµ-myc Pin1-/- B-cells showed reduced activation of Myc-induced mRNAs
relative to Eµ-myc Pin1+/+ cells, experiments in MEFs demonstrated that
the overall transcriptional activity of Myc was independent from Pin1.
Furthermore, upon ablation of p53, Myc-induced lymphomas progressed with
or without Pin1, and with an equally fast course. Thus, while Pin1 is not
essential for normal cell growth and mouse development, it is required to
support the oncogenic activity of Myc in B-cells, most likely via the
selective suppression of a p53-dependent growth-inhibitory
checkpoint.<br><br>
Host: ARK<br><br>
-- <br>
Francisco J. Urbano, PhD.<br>
IFIBYNE-CONICET<br>
Intendente Güiraldes 2160 <br>
Facultad Ciencias Exactas<br>
Pabellon 2- Piso 2<br>
Ciudad Universitaria<br>
(C1428EGA) Buenos Aires<br>
ARGENTINA<br>
Email:
<a href="mailto:fjurbano@fbmc.fcen.uba.ar">fjurbano@fbmc.fcen.uba.ar</a>
,<br>
<a href="mailto:fran.j.urbano@gmail.com">fran.j.urbano@gmail.com</a><br>
Phone: (+54)-11-4576 3368<br>
Fax: (+54)-11-4576 3321<br>
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