TUMOR-SUPPRESSOR PROTEINS AS REGULATORS OF CELL-DIFFERENTIATION

The products of the tumor suppressor genes are considered to function as specific inhibitors of tumor cell growth. In this communication, we present evidence to show that these proteins inhibit tumor cell proli feration by participating in the activation of tumor cell differentiat ion. The ML-1 human myeloblastic leukemia cells used in this study pro liferate when treated with insulin-like growth factor I and transferri n but differentiate to monocytes when exposed to tumor necrosis factor alpha or transforming growth factor beta 1, or to macrophage-like cel ls when treated with both these cytokines, Initiation of proliferation hut not of differentiation was followed by a 20- to 25-fold increase in the nuclear Level of the DNA polymerase-associated processivity fac tor PCNA and of the proliferation-specific transcription factor E2F1. In contrast, induction of differentiation but not of proliferation was followed by a 25- to 30-fold increase in the nuclear level of the tum or suppressor proteins p53 (wild type), pRb, and p130/Rb2 and of the p 53-dependent cyclin kinase inhibitor p21/Cip1, p53 and p21/Cip1, respe ctively, inhibit the expression and activation of PCNA, whereas p130 a nd pRb, respectively, inhibit the expression and activation of E2F1. A s a result, G(1)-S-associated DNA and mRNA synthesis is inhibited, gro wth uncoupled from differentiation, and maturation enabled to proceed. Where this function of the tumor suppressor proteins is impaired, the capacity for differentiation is Lost, which Leads to the sustained pr oliferation that is characteristic of the cancer cell.