Journal Article

Functional impact of cancer-associated mutations in the tumor suppressor protein ING4

Alberto Moreno, Alicia Palacios, Jose Luis Orgaz, Benilde Jimenez, Francisco J. Blanco and Ignacio Palmero

in Carcinogenesis

Volume 31, issue 11, pages 1932-1938
Published in print November 2010 | ISSN: 0143-3334
Published online August 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq171
Functional impact of cancer-associated mutations in the tumor suppressor protein ING4

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Inhibitor of growth 4 (ING4) is a member of the ING family of tumor suppressor proteins. In this study, we have analyzed the impact of two mutations in ING4 associated with human tumors (Y121N and N214D), testing their behavior in a series of functional, biochemical and structural analyses. We report that the N214D mutation dramatically dampened the ability of ING4 to inhibit proliferation, anchorage-independent growth or cell migration or to sensitize to cell death. In turn, the Y121N mutant did not differ significantly from wild-type ING4 in our assays. Neither of the mutations altered the normal subcellular localization of ING4, showing predominantly nuclear accumulation. We investigated the molecular basis of the defect in the activity of the N214D mutant. The folding and ability to bind histone marks of ING4 was not significantly altered by this mutation. Instead, we found that the functional impairment of the N214D mutant correlates with reduced protein stability due to increased proteasome-mediated degradation. In summary, our data demonstrates that a point mutation of ING4 associated to human tumors leads to the loss of several essential functions of ING4 pertinent to tumor protection and highlight the importance of ING4 function to prevent tumorigenesis.

Journal Article.  5373 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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