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Exclusion of c-Abl from the nucleus restrains the p73 tumor suppression function
Veronica Vella1, Jiangyu Zhu, Francesco Frasca
1Division of Biological Sciences and the Cancer Center, University of California, San Diego, La Jolla 92093-0322, USA.
Abstract:
The p73alpha protein is a functional homolog of the p53 tumor suppressor. Although the TP53 gene is frequently mutated in human cancers, the TP73 gene is rarely inactivated. We have found that p73alpha is highly expressed in a significant fraction of anaplastic thyroid cancer, whereas it is not detectable in normal thyroid epithelial cells or in papillary and follicular thyroid cancer cells. Interestingly, the tumor suppression function of p73alpha is actively restrained in anaplastic thyroid cancer cells. We have also found that c-Abl tyrosine kinase, an activator of p73, is excluded from the nucleus of p73alpha-positive thyroid cancer cells; whereas c-Abl undergoes nuclear-cytoplasmic shuttling in normal thyroid and p73-negative thyroid cancer cells. We constructed an AblNuk-FK506-binding protein (FKBP) fusion protein to enforce the nuclear accumulation of an inducible Abl kinase. Activation of this nuclear AblNuk-FKBP by dimerization with AP20187 in anaplastic thyroid cancer cells increased the levels of p73alpha and p21Cip1 and caused p73-dependent apoptosis. These results suggest subcellular segregation of c-Abl from p73 to be a strategy for disrupting the tumor suppression function of p73alpha.
Insights
p73alpha protein, a tumor suppressor, is highly expressed in anaplastic thyroid cancer but its function is restrained. Nuclear exclusion of c-Abl kinase disrupts p73alpha
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- p73alpha protein functions as a tumor suppressor, analogous to p53.
- Unlike TP53, the TP73 gene is seldom inactivated in human cancers.
- p73alpha is notably absent in normal thyroid cells and differentiated thyroid cancers (papillary, follicular).
Purpose of the Study:
- Investigate the role of p73alpha in anaplastic thyroid cancer (ATC).
- Determine the mechanism restraining p73alpha's tumor suppressor activity in ATC.
- Explore the interaction between c-Abl tyrosine kinase and p73alpha in thyroid cancer.
Main Methods:
- Quantitative analysis of p73alpha expression in various thyroid tissues.
- Assessment of c-Abl kinase localization (nuclear vs. cytoplasmic).
- Development and application of a fusion protein (AblNuk-FKBP) to induce nuclear c-Abl accumulation.
Main Results:
- p73alpha is highly expressed in ATC but its tumor suppressive function is inhibited.
- c-Abl tyrosine kinase is excluded from the nucleus in p73alpha-positive ATC cells.
- Forced nuclear localization of c-Abl in ATC cells reactivated p73alpha, increased p21Cip1, and induced apoptosis.
Conclusions:
- Subcellular segregation of c-Abl from p73alpha is a mechanism for inactivating p73alpha's tumor suppressor function in ATC.
- Restoring nuclear c-Abl activity in ATC cells can potentially overcome p73alpha inhibition and induce cancer cell death.
- Targeting the c-Abl/p73alpha interaction may offer a therapeutic strategy for anaplastic thyroid cancer.