Objective: The cyclin-dependent kinase inhibitor 1A (CDKN1A), p21/Cipl, is a vital cell cycle regulator, dysregulation of which has been associated with a large number of human malignancies.One critical mechanism that controls p21 function is through its degradation that allows the activation of its associated cell cycle promoting kinases,CDK2 and CDK4.Thus, delineating how p21 is stabilized and degraded will enhance our understanding of the cell growth control and offer basis for potential therapeutic interventions.Methods: The protein interactions were assessed by GST pull-down and co-immunoprecipitation assays.The cell cycle distribution and cell apoptosis were detected using PI and Annexin V-FITC/PI staining by flow cytometric analysis.The expression level of proteins and mRNA were analysed by western blot,immunohistochemistry and RT-PCR.Results: Here we report a novel regulatory mechanism that controls dynamic status of p21 through its interaction with Cdk5 and Abl enzyme substrate 1 (Cables1).Cables1 has a proposed role as a tumor suppressor.We found that the upregulated protein level of Cables1 was correlated with increased half-life of p21 protein, which was attributed to the Cables1/p21 complex formation and supported by their co-localization in the nucleus.Mechanistically, Cablesl competes with proteasome subunit PSMA3 to bind to p21 and protects p21 from PSMA3-mediated proteasomal degradation.Moreover, silencing of p21 partially reverses the function of Cables 1 to induce cell death and inhibit cell proliferation.In further support of a potential pathophysiological role of Cables1, the expression level of Cables1 is tightly associated with p21 in both cancer cell lines and human lung cancer patient tumor samples.Conclusions: Together, these results suggest Cablesl as a novel p21 regulator through maintaining p21 stability, and support the model that the tumor suppression function of Cables 1 is at least in part through enhancing the tumor suppression activity of p21.