CCAAT/Enhancer Binding Protein alpha uses distinct domains to prolong pituitary cells in the Growth 1 and DNA Synthesis phases of the cell cycle
1 Metabolic Research Unit, Diabetes Research Center and Department of Medicine, University of California, San Francisco, CA, 94143-0540, USA
2 Comprehensive Cancer Center, University of California, San Francisco, CA, 94143, USA
3 Departments of Medicine and Cell Biology, NSF Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville, Virginia, 22908, USA
4 Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA, 94080, USA
5 Department of Biology, Austin College, Sherman, TX, 75090, USA
BMC Cell Biology 2002, 3:6 doi:10.1186/1471-2121-3-6Published: 21 March 2002
A number of transcription factors coordinate differentiation by simultaneously regulating gene expression and cell proliferation. CCAAT/enhancer binding protein alpha (C/EBPα) is a basic/leucine zipper transcription factor that integrates transcription with proliferation to regulate the differentiation of tissues involved in energy balance. In the pituitary, C/EBPα regulates the transcription of a key metabolic regulator, growth hormone.
We examined the consequences of C/EBPα expression on proliferation of the transformed, mouse GHFT1-5 pituitary progenitor cell line. In contrast to mature pituitary cells, GHFT1-5 cells do not contain C/EBPα. Ectopic expression of C/EBPα in the progenitor cells resulted in prolongation of both growth 1 (G1) and the DNA synthesis (S) phases of the cell cycle. Transcription activation domain 1 and 2 of C/EBPα were required for prolongation of G1, but not of S. Some transcriptionally inactive derivatives of C/EBPα remained competent for G1 and S phase prolongation. C/EBPα deleted of its leucine zipper dimerization functions was as effective as full-length C/EBPα in prolonging G1 and S.
We found that C/EBPα utilizes mechanistically distinct activities to prolong the cell cycle in G1 and S in pituitary progenitor cells. G1 and S phase prolongation did not require that C/EBPα remained transcriptionally active or retained the ability to dimerize via the leucine zipper. G1, but not S, arrest required a domain overlapping with C/EBPα transcription activation functions 1 and 2. Separation of mechanisms governing proliferation and transcription permits C/EBPα to regulate gene expression independently of its effects on proliferation.