Cloning of mid-G1 serum response genes and identification of a subset regulated by conditional myc expression

SV Tavtigian, SD Zabludoff and BJ Wold

Myriad Genetics, Salt Lake City, Utah 84108.

The emergence of cells from a quiescent G0 arrested state into the cell cycle is a multistep process that begins with the immediate early response to mitogens and extends into a specialized G1 phase. Many immediate early serum response genes including c-fos, c-myc, and c-jun are transcriptional regulators. To understand their roles in regulating cell cycle entry and progression, the identities of their regulatory targets must be determined. In this work we have cloned cDNA copies of messenger RNAs that are either up- or down-regulated at a mid-G1 point in the serum response (midserum-response [mid-SR]). The mid-SR panel is expected to include both direct and indirect targets of immediate early regulators. This expectation was confirmed by the identification of several transcriptional targets of conditional c-myc activity. In terms of cellular function, the mid-SR class is also expected to include execution genes needed for progression through G1 and into S-phase. DNA sequence data showed that the mid-SR panel included several genes already known to be involved in cell cycle progression or growth transformation, suggesting that previously unknown cDNAs in the same group are good candidates for other G1 execution functions. In functional assays of G0-->S-phase progression, c-myc expression can bypass the requirement for serum mitogens and drive a large fraction of G0 arrested cells through G1 into S-phase. However, beyond this general similarity, little is known about the relation of a serum-driven progression to a myc-driven progression. Using the mid-SR collection as molecular reporters, we found that the myc driven G1 differs qualitatively from the serum driven case. Instead of simply activating a subset of serum response genes, as might be expected, myc regulated some genes inversely relative to serum stimulation. This suggests that a myc driven progression from G0 may have novel properties with implications for its action in oncogenesis.

Volume 5, Issue 3, pp. 375-388, 03/01/1994
Copyright © 1994 by The American Society for Cell Biology

This article has been cited by other articles:

				M. Dose, I. Khan, Z. Guo, D. Kovalovsky, A. Krueger, H. von Boehmer, K. Khazaie, and F. Gounari c-Myc mediates pre-TCR-induced proliferation but not developmental progression Blood, October 15, 2006; 108(8): 2669 - 2677. [Abstract] [Full Text] [PDF]

				S. R. Frank, M. Schroeder, P. Fernandez, S. Taubert, and B. Amati Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation Genes & Dev., August 15, 2001; 15(16): 2069 - 2082. [Abstract] [Full Text] [PDF]

				K. E. Boyd and P. J. Farnham Identification of Target Genes of Oncogenic Transcription Factors Experimental Biology and Medicine, October 2, 1999; 222(1): 9 - 28. [Abstract] [Full Text]

				I. Ben-Porath, O. Yanuka, and N. Benvenisty The Tmp Gene, Encoding a Membrane Protein, Is a c-Myc Target with a Tumorigenic Activity Mol. Cell. Biol., May 1, 1999; 19(5): 3529 - 3539. [Abstract] [Full Text] [PDF]

				C. V. Dang c-Myc Target Genes Involved in Cell Growth, Apoptosis, and Metabolism Mol. Cell. Biol., January 1, 1999; 19(1): 1 - 11. [Full Text] [PDF]

				H. Shim, C. Dolde, B. C. Lewis, C.-S. Wu, G. Dang, R. A. Jungmann, R. Dalla-Favera, and C. V. Dang c-Myc transactivation of LDH-A: Implications for tumor metabolism and growth PNAS, June 24, 1997; 94(13): 6658 - 6663. [Abstract] [Full Text] [PDF]

				L Desbarats, S Gaubatz, and M Eilers Discrimination between different E-box-binding proteins at an endogenous target gene of c-myc. Genes & Dev., February 15, 1996; 10(4): 447 - 460. [Abstract] [PDF]

				V. Taylor, A. A. Welcher, A. E. Program, and U. Suter Epithelial Membrane Protein-1, Peripheral Myelin Protein 22, and Lens Membrane Protein 20 Define a Novel Gene Family J. Biol. Chem., December 1, 1995; 270(48): 28824 - 28833. [Abstract] [Full Text] [PDF]

				P. J. Donohue, G. F. Alberts, Y. Guo, and J. A. Winkles Identification by Targeted Differential Display of an Immediate Early Gene Encoding a Putative Serine/Threonine Kinase J. Biol. Chem., April 28, 1995; 270(17): 10351 - 10357. [Abstract] [Full Text] [PDF]

				R. Drissi, F. Zindy, M. F. Roussel, and J. L. Cleveland c-Myc-mediated Regulation of Telomerase Activity Is Disabled in Immortalized Cells J. Biol. Chem., August 3, 2001; 276(32): 29994 - 30001. [Abstract] [Full Text] [PDF]