Clefts, grooves, and (small) pockets: The structure of the retinoblastoma tumor suppressor in complex with its cellular target E2F unveiled
- Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Armenise Research Building 544A, Boston, MA 02115-5701
Tumor suppressors are functional antagonists of oncogenes and their loss of function importantly contributes to human carcinogenesis. The sequence of the first human tumor suppressor, the retinoblastoma susceptibility gene product pRb, was published in 1986 (1). In this issue of PNAS, Xiao et al. (2) report the crystal structure of a pRb fragment in complex with a peptide derived from the E2F transcription factor, a key cellular target of pRb. An article by Lee et al. (3) recently published elsewhere reports similar findings. Thus, in less than four National Institutes of Health grant funding cycles since its initial discovery, we have arrived at a detailed structural understanding of how pRb inhibits cell growth, how this activity is regulated in normal cells, and how pRb is put out of action in tumor cells.
Loss of pRb function is the rate-limiting step in the development of retinoblastoma, a rare childhood eye tumor. There is compelling evidence that pRb is at the center of a crucial cellular regulatory circuit that is perturbed in most human tumors (reviewed in ref. 4) (Fig. 1). Thus, the pRb pathway offers attractive targets for cancer therapy, and the delineation of the E2F/pRb structure is good news and highly significant.
The retinoblastoma tumor suppressor pathway contains multiple oncogenes (green) and tumor suppressors (red) and is dysfunctional in almost every human tumor. Even though E2F is an important mediator of the growth suppressor function of pRb, no activating E2F mutants have been detected in human tumors.
One important function of pRb is to inhibit cellular DNA synthesis. In resting cells, pRb is hypophosphorylated and in complex with E2F, a group of heterodimeric transcription factors consisting of an E2F family member (E2F-1 to 6) and a dimerization partner (DP-1 or DP-2) (reviewed in ref. 5). E2F/pRb complexes are transcriptional …
