The retinoblastoma gene (RB) was identified because of germ-line mutations that strongly predisposed infants with the mutant gene to a rare cancer of the retina. However, the RB protein turned out to be a regulator of transcription in all cells of adults. The active form of the protein represses the expression of genes required for cells to proceed through the cycle of cell division. Phosphorylation, mediated by a complex of several proteins regulated by the cell cycle (a cyclin and a cyclin-dependent kinase), inactivates the RB protein, allowing cell division to begin.

It is easy to understand that mutations resulting in defective or absent RB protein would be advantageous for cell proliferation and would initiate a cancer or contribute to increasing the malignancy of a preexisting cancer. Cryns et al. suggest in this issue of the Journal (see pages 757 to 761) that loss of RB protein is very common among parathyroid carcinomas but not parathyroid adenomas. Parathyroid adenomas frequently overexpress cyclin D1 because of somatic chromosomal rearrangements that bring the cyclin D1 gene (PRAD1) under control of the parathyroid hormone gene enhancer and thus result in high levels of expression in parathyroid tissue. Cyclin D1 can phosphorylate and inactivate RB protein. However, the association of RB mutation with parathyroid carcinoma suggests that cyclin D1 only partly inactivates RB protein, since RB gene mutation results in further growth advantage for that clone.

The tissue specificities for the initiation and progression of cancer resulting from RB gene mutations suggest that initiation and progression may be separate processes (Figure 1). Humans with one mutant germ-line RB allele are normal except for their susceptibility to cancer; their risk for the development of retinoblastoma in the first years of life is 36,000 times that of people without the mutation. Interestingly, in mice with germ-line RB mutations, it is not retinoblastoma that develops but pituitary tumors instead. Humans with germ-line RB mutations also have 2000 times the normal risk of osteosarcoma during the second decade of life and an undefined, but lower, risk of other tumors, such as melanoma and soft-tissue sarcoma. Neither parathyroid nor pituitary tumors, however, occur at an increased rate in humans with these mutations.

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