The team found that when RB alone was switched off, the cells could not efficiently undergo this process of oncogene-induced senescence. When these cells lost RB activity, they could not shut off DNA replication, began to replicate out of control and developed genomic instability. "These aberrant processes, when exacerbated by breakdowns in other control mechanisms, lead to the development of malignant tumors," says Agustin Chicas, Ph.D., a postdoctoral fellow working with Dr. Lowe and the lead investigator in the study.

Further investigations showed that a key target of RB is a gene called cyclin E1, which has been found to be overactive in many human tumors and is often associated with poor prognosis in patients. Its normal function is to spur DNA replication during the cell cycle and hence it is tightly suppressed by RB in senescent cells. The team showed that the loss of RB frees cyclin E1, thus allowing cells to escape senescence.

"Our team's findings suggest that the selective targeting of DNA replication genes during senescence represents one key activity of RB in tumor suppression," says Lowe.

"Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence," appears online on April 13th in Cancer Cell. The full citation is: Agustin Chicas, Xiaowo Wang, Chaolin Zhang, Mila McCurrach, Zhen Zhao, Ozlem Mert, Ross A. Dickins, Masashi Narita, Michael Zhang, Scott W. Lowe. The paper is available at cell/cancer-cell/abstract/S1535-6108(10)00072-3.

Source: Cold Spring Harbor Laboratory