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Regulation of survivin function by Hsp90

Paola FortugnoDepartment of Cancer Biology and Cancer Center, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605; Departments of Pharmacology and Pathology, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536; and Department of Biological and Technological Research, Università Vita-Salute San Raffaele School of Medicine, Via Olgettina 58, 20132 Milan, ItalyElena BeltramiDepartment of Cancer Biology and Cancer Center, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605; Departments of Pharmacology and Pathology, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536; and Department of Biological and Technological Research, Università Vita-Salute San Raffaele School of Medicine, Via Olgettina 58, 20132 Milan, ItalyJanet PlesciaDepartment of Cancer Biology and Cancer Center, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605; Departments of Pharmacology and Pathology, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536; and Department of Biological and Technological Research, Università Vita-Salute San Raffaele School of Medicine, Via Olgettina 58, 20132 Milan, ItalyJason FontanaDepartment of Cancer Biology and Cancer Center, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605; Departments of Pharmacology and Pathology, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536; and Department of Biological and Technological Research, Università Vita-Salute San Raffaele School of Medicine, Via Olgettina 58, 20132 Milan, ItalyDeepti PradhanDepartment of Cancer Biology and Cancer Center, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605; Departments of Pharmacology and Pathology, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536; and Department of Biological and Technological Research, Università Vita-Salute San Raffaele School of Medicine, Via Olgettina 58, 20132 Milan, ItalyPier Carlo MarchisioDepartment of Cancer Biology and Cancer Center, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605; Departments of Pharmacology and Pathology, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536; and Department of Biological and Technological Research, Università Vita-Salute San Raffaele School of Medicine, Via Olgettina 58, 20132 Milan, ItalyWilliam C. SessaDepartment of Cancer Biology and Cancer Center, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605; Departments of Pharmacology and Pathology, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536; and Department of Biological and Technological Research, Università Vita-Salute San Raffaele School of Medicine, Via Olgettina 58, 20132 Milan, ItalyDario C. AltieriDepartment of Cancer Biology and Cancer Center, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605; Departments of Pharmacology and Pathology, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536; and Department of Biological and Technological Research, Università Vita-Salute San Raffaele School of Medicine, Via Olgettina 58, 20132 Milan, Italy

2003en

ABI

Annotatsiya

Pathways controlling cell proliferation and cell survival require flexible adaptation to environmental stresses. These mechanisms are frequently exploited in cancer, allowing tumor cells to thrive in unfavorable milieus. Here, we show that Hsp90, a molecular chaperone that is central to the cellular stress response, associates with survivin, an apoptosis inhibitor and essential regulator of mitosis. This interaction involves the ATPase domain of Hsp90 and the survivin baculovirus inhibitor of apoptosis repeat. Global suppression of the Hsp90 chaperone function or targeted Abmediated disruption of the survivin-Hsp90 complex results in proteasomal degradation of survivin, mitochondrial-dependent apoptosis, and cell cycle arrest with mitotic defects. These data link the cellular stress response to an antiapoptotic and mitotic checkpoint maintained by survivin. Targeting the survivin-Hsp90 complex may provide a rational approach for cancer therapy.

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DOI: 10.1073/pnas.2434345100

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