Yen A, Varvayanis S
Department of Pathology, Cornell University, Ithaca, New York 14853, USA.
J Cell Physiol. 1995 Jun;163(3):502-9. doi: 10.1002/jcp.1041630310.
To examine the potential coupling between inducible cellular changes in RB (retinoblastoma) tumor suppressor protein phosphorylation and ability to G0 growth arrest and differentiate, HL-60 promyelocytic leukemia cells were cultured in incremental sodium butyrate (NaB) concentrations and thereby made resistant to the growth inhibitory effects of sodium butyrate, which normally induces G0 arrest and monocytic differentiation in wild type HL-60 cells. The resistant cells were also unable to differentiate in response to NaB, indicating that a regulatory function controlling both G0 growth arrest and differentiation had been affected. The induced resistance was not genetic in origin since the cells regained the ability to G0 arrest and differentiate after being recultured in medium free of sodium butyrate for only three days. The resistant cells had similar cell cycle phase durations as the original wild type cells. The resistant cells retained the ability to both G0 arrest and differentiate in response to 1,25-dihydroxy vitamin D3 (VD3), normally an inducer of G0 arrest and monocytic differentiation in wild type cells. However, they were cross-resistant to retinoic acid (RA), another ligand for the same steroid thyroid hormone receptor family, which induces G0 arrest and myeloid differentiation in wild type cells. The ability to G0 arrest and phenotypically differentiate in response to RA were both grossly impaired. Unlike wild type cells which undergo early down-regulation and then hypophosphorylation of the RB protein when induced to differentiate, in resistant cells, hypophosphorylation of RB in response to NaB was grossly retarded. These changes in RB protein occurred faster when the cells were treated with VD3. In contrast, the changes in RB phosphorylation occurred significantly slower when the cells were treated with RA. The results suggest a coupling between the ability to G0 growth arrest and phenotypically convert and the ability to hypophosphorylate RB.
