Thomas Chittenden (Immunogen Inc., Cambridge, Mass.): "This work was done in the lab of David M. Livingston at the Dana- Farber Cancer Institute in Boston. The retinoblastoma protein (Rb) belongs to a class of growth regulatory proteins, termed tumor suppressors, which function to prevent tumorigenesis. Livingston's laboratory has been interested in understanding, at a molecular level, how Rb negatively regulates cell growth. In 1991 several groups, including our own, demonstrated that Rb forms a complex with the cellular transcription factor E2F. E2F contributes to the cell cycle-dependent transcription of a multitude of genes involved in DNA synthesis and cell proliferation.
"This work is an effort to understand how the activity of E2F is coordinated with the cell cycle. We show that regulation of E2F involves an interaction with Rb in G1, whereas in S phase, E2F forms a complex with an Rb-related protein, p107, and cyclin A. Similar findings were reported simultaneously by several other laboratories.
"The interest in this paper most likely reflects a convergence of several areas of intensive research: Rb (tumor suppressors), E2F (transcription factors), and cyclins (components of the cell cycle machinery). These findings provide evidence that different members of the Rb protein family (Rb and p107) have distinct functions in the cell cycle. The presence of cyclin A, a known regulator of S phase, in a DNA-binding transcription factor complex is provocative to many investigators.
"Subsequent studies by a number of groups have pointed to additional complexity in virtually every component of E2F regulation. The recent isolation of cDNA clones for E2F has revealed that E2F is actually a family of proteins. At least one other cyclin, cyclin E, interacts with E2F, but with kinetics that are distinct from cyclin A. There is also evidence that yet additional members of the Rb protein family interact with E2F. Despite the incredibly rapid pace of research in this area, the central challenge remains to determine how all of these components are integrated to provide appropriate cell cycle-dependent transcription of E2F-responsive genes."