title: Targeting the β-catenin nuclear transport pathway in cancer.
abstract: The nuclear localization of specific proteins is critical for cellular processes such as cell division, and in recent years perturbation of the nuclear transport cycle of key proteins has been linked to cancer. In particular, specific gene mutations can alter nuclear transport of tumor suppressing and oncogenic proteins, leading to cell transformation or cancer progression. This review will focus on one such factor, β-catenin, a key mediator of the canonical wnt signaling pathway. In response to a wnt stimulus or specific gene mutations, β-catenin is stabilized and translocates to the nucleus where it binds TCF/LEF-1 transcription factors to transactivate genes that drive tumor formation. Moreover, the nuclear import and accumulation of β-catenin correlates with clinical tumor grade. Recent evidence suggests that the primary nuclear transport route of β-catenin is independent of the classical Ran/importin import machinery, and that β-catenin directly contacts the nuclear pore complex to self-regulate its own entry into the nucleus. Here we propose that the β-catenin nuclear import pathway may provide an opportunity for identification of specific drug targets and inhibition of β-catenin nuclear function, much like the current screening of drugs that block binding of β-catenin to LEF-1/TCFs. Here we will discuss the diverse mechanisms regulating nuclear localization of β-catenin and their potential as targets for anticancer agent development.
authors.affiliation: Westmead Institute for Cancer Research, The University of Sydney, Westmead Millennium Institute at Westmead Hospital, Westmead, NSW 2145, Australia.
authors.forename: Cara
authors.initials: C
authors.lastname: Jamieson
authors.affiliation: Westmead Institute for Cancer Research, The University of Sydney, Westmead Millennium Institute at Westmead Hospital, Westmead, NSW 2145, Australia.
authors.forename: Manisha
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Westmead Institute for Cancer Research, The University of Sydney, Westmead Millennium Institute at Westmead Hospital, Westmead, NSW 2145, Australia. Electronic address: beric.henderson@sydney.edu.au.
authors.forename: Beric R
authors.initials: BR
authors.lastname: Henderson
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051176:beta Catenin
keywords: Cancer; Nuclear envelope; Nuclear transport; Wnt signaling; β-Catenin