SIGNALING BY ABL ONCOGENES THROUGH CYCLIN D1

Oncogenic signals induce cellular proliferation by deregulating the cell division cycle. Cyclin D1, a regulator of G(1)-phase progression, acts synergistically with ABL oncogenes in transforming fibroblasts and hematopoietic cells in culture. Synergy with v-Abl depended on a motif in cyclin D1 that mediates its binding to the retinoblastoma protein, suggesting that ABL oncogenes in part mediate their mitogenic effects via a retinoblastoma protein-dependent pathway. Overexpression of cyclin D1, but not cyclin E, rescued a signaling-defective src-homology 2 (SH2) domain mutant of BCR-RBL for transformation of cells in culture and malignant tumor formation in vivo. These results demonstrate that cyclin D1 can provide essential signals for malignant transformation in concert with an activated tyrosine kinase.