Cyclin D1 Regulatory Pathways are Targeted in Human Cancer. Cyclin D1 protein accumulation is tightly controlled via phosphorylation-dependent proteolysis. Mutations targeting cyclin D1 phosphorylation or degradation contribute to neoplastic transformation. Specific disruption of Thr-286 phosphorylation occurs in endometrial and esophageal carcinoma, while mutations preventing Crm1 binding occur in endometrial cancer. Mutations targeting Fbx4 have been identified in esophageal cancer, and αB crystallin loss occurs in tumor-derived breast carcioma cell lines. Disruption of cyclin D1 proteolysis promotes accumulation of active cyclin D1/CDK4 kinase, triggering DNA re-replication and subsequent genomic instability necessary to drive neoplastic transformation.