Qemo, I. | Search bioRxiv

bioRxiv2023

Atypical Cell Cycle Regulation over Neural Stem Cell Expansion

Populations of adult neural stem cells (NSCs) that reside in the mammalian brain aid in neurogenesis throughout life and can be identified by a type VI intermediate filament protein, Nestin. Cell cycle regulation plays an important role in maintaining a balance between self-renewal and differentiation and determining the fate of NSCs. Data from our group and others support that the atypical cyclin-like protein Spy1 (also called RingoA; gene SPDYA) plays a critical role in activating NSCs from a quiescent state. Elevated levels of Spy1 are found in aggressive human brain cancers, including glioblastoma. Using a conditional mouse model, we demonstrate that driving the expression of Spy1, in the Nestin-enriched NSC population of the brain, increases stemness characteristics, decreases differentiation, and increases susceptibility to oncogenic transformation. This study contributes to better understanding of intricate cell cycle mechanisms which lead to deviation from the homeostatic state, promoting aberrant changes in adult NSCs.

molecular biology↗

bioRxiv2019

The Atypical Cyclin-Like Protein Spy1 Overrides p53-Mediated Tumour Suppression and Promotes Susceptibility to Breast Tumorigenesis

Breast cancer is the most common cancer to affect women and one of the leading causes of cancer related deaths. Maintenance of genomic stability and proper regulation of cell cycle checkpoints play a critical role in preventing the accumulation of deleterious mutations. Perturbations in the expression or activity of mediators of cell cycle progression or checkpoint activation represent important events that may increase susceptibility to the onset of carcinogenesis. The atypical cyclin-like protein Spy1 was isolated in a screen for novel genes that could bypass the DNA damage response. Clinical data demonstrates that protein levels of Spy1 are significantly elevated in ductal and lobular carcinoma of the breast. Using a transgenic mouse driving expression of Spy1 in the mammary epithelium we demonstrate that sustained elevation of Spy1 leads to enhanced proliferation and an increased susceptibility to mammary tumour formation. We find that Spy1 is targeted for degradation by the tumour suppressor p53 to protect checkpoint control. When crossed with p53 deficient mice, elevation of Spy1 leads to an increase in hyperplastic alveolar nodules. Targeting cyclin-like protein activity may therefore represent a mechanism of re-sensitizing cells to important cell cycle checkpoints in a therapeutic setting.

cancer biology↗