Abstract
BackgroundSpy1 is a novel 'cyclin-like' activator of the G1/S transition capable of enhancing cell proliferation as well as inhibiting apoptosis. Spy1 protein levels are tightly regulated during normal mammary development and forced overexpression in mammary mouse models accelerates mammary tumorigenesis.MethodsUsing human tissue samples, cell culture models and in vivo analysis we study the implications of Spy1 as a mediator of mammary transformation and breast cancer proliferation.ResultsWe demonstrate that this protein can facilitate transformation in a manner dependent upon the activation of the G2/M Cdk, Cdk1, and the subsequent inhibition of the anti-apoptotic regulator FOXO1. Importantly, we show for the first time that enhanced levels of Spy1 protein are found in a large number of human breast cancers and that knockdown of Spy1 impairs breast cancer cell proliferation.ConclusionsCollectively, this work supports that Spy1 is a unique activator of Cdk1 in breast cancer cells and may represent a valuable drug target and/or a prognostic marker for subsets of breast cancers.
Highlights
Spy1 is a novel ‘cyclin-like’ activator of the G1/S transition capable of enhancing cell proliferation as well as inhibiting apoptosis
Using approximately half the amount of transfected DNA for Spy1-TST resulted in a statistically significant reduction of overall protein levels of ~30%, but at least a 2-fold increase in colony formation with high statistical significance. This suggests the possibility that threshold levels or stabilization of the Spy1 protein triggers a unique mechanism that may contribute toward Spy1-mediated tumorigenesis
Collectively, this work supports that critical levels of Spy1 protein trigger transformation dependent upon the activation of the G2/M cyclin-dependent kinase, Cdk1
Summary
Spy is a novel ‘cyclin-like’ activator of the G1/S transition capable of enhancing cell proliferation as well as inhibiting apoptosis. Spy protein levels are tightly regulated during normal mammary development and forced overexpression in mammary mouse models accelerates mammary tumorigenesis. The Speedy/RINGO family of proteins are novel regulators of the cell cycle, capable of activating the cyclindependent kinases (Cdks) independent of cyclin binding and phosphorylation within the Cdk T-loop [1]. The human Speedy/RINGO homolog, referred to as Spy, is constitutively expressed in most human tissues and is essential for somatic cell cycle progression [2]. Ectopic expression of Spy promotes rapid cell cycle progression through G1/S phase that is attributed, at least in part, to the activation of Cdk2 [2].
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