| 摘要 |
Spy1A is a cyclin-like protein required for progression through the Gj/S phase of the cell cycle. Overexpression of Spy1A is sufficient to override the DNA damage response and to support enhanced cell proliferation; accordingly aberrant levels of this protein have been implicated in tumorigenesis. Understanding how Spy1A is produced and degraded is essential in resolving how it contributes to normal and abnormal growth processes. Herein, we demonstrate that Spy1A is degraded in a cell-cycle-dependent manner via the ubiquitin-proteasome system. We have resolved that the E3 ligase mediating degradation during the somatic cell cycle is in fact Nedd4, a protein responsible for the degradation of several important cellular oncogenes and tumor suppressor genes. In addition, we have identified the phosphorylation sites on Spy1A which mediate its degradation and we have resolved that non-degradable forms of Spy1A do not trigger cell cycle arrest but rather contribute to uncontrolled cell growth. Importantly, this work connects two proteins previously implicated in carcinogenesis, Spy1A and Nedd4. Further investigation into the regulation of Spy1lA may reveal novel strategies for understanding the etiology and progression of specific growth disorders. Aberrant levels Spy1A protein have been implicated in, many forms of cancer, developmental disorders, neurodegenerative disorders, diabetes and are attributed to overriding the DNA damage response and enhancing cell proliferation. Understanding how Spy1A is produced and degraded is essential in resolving how it contributes to normal and abnormal growth process, this process represents a novel mechanism for the development of agents and therapeutic treatments for these disorders. These technologies also represent effective strategies for regenerative medicine. Furthermore, protein levels of Spy1A represent a valuable diagnostic and prognostic marker for many forms of cancer, development disorders, neurodegenerative disorders and diabetes applicable to all vertebrates.
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