Research Summary: Aberrant Anaplastic Lymphoma Kinase Activity Induces a p53 and Rb-Dependent Senescence-Like Arrest in the Absence of Detectable p53 Stabilization


Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase aberrantly
expressed in a variety of tumor types, most notably in Anaplastic Large Cell
Lymphoma (ALCL) where a chromosomal translocation generates the oncogenic fusion
protein, Nucleophosmin-ALK (NPM-ALK). Whilst much is known regarding the
mechanism of transformation by NPM-ALK, the existence of cellular defence
pathways to prevent this pathological process has not been investigated.
Employing the highly tractable primary murine embryonic fibroblast (MEF) system
we show that cellular transformation is not an inevitable consequence of NPM-ALK
activity but is combated by p53 and Rb. Activation of p53 and/or Rb by NPM-ALK
triggers a potent proliferative block with features reminiscent of senescence.
While loss of p53 alone is sufficient to circumvent NPM-ALK-induced senescence
and permit cellular transformation, sole loss of Rb permits continued
proliferation but not transformation due to p53-imposed restraints. Furthermore,
NPM-ALK attenuates p53 activity in an Rb and MDM2 dependent manner but this
activity is not sufficient to bypass senescence. These data indicate that
senescence may constitute an effective barrier to ALK-induced malignancies that
ultimately must be overcome for tumor development.


Publisher: Public Library of Science

Date Published: 14-March-2011

Author(s): McDuff F., Turner S.


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