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Published March 1, 1994 | Published
Journal Article Open

Cloning of mid-G_1 serum response genes and identification of a subset regulated by conditional myc expression


The emergence of cells from a quiescent G_0 arrested state into the cell cycle is a multistep process that begins with the immediate early response to mitogens and extends into a specialized G_1 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-G_1 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 G_1 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 G_1 execution functions. In functional assays of G_0-->S-phase progression, c-myc expression can bypass the requirement for serum mitogens and drive a large fraction of G_0 arrested cells through G_1 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 G_1 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 G_0 may have novel properties with implications for its action in oncogenesis.

Additional Information

© 1994 by The American Society for Cell Biology. Submitted December 6, 1993; Accepted January 14, 1994. We are indebted to N. Cowan, T. Curran, L. Moran, I. Verma, R. Weinberg, and R. Benezra for β-tubulin, fra-1, hsp 70, c-fos, p53, and Id cDNAs, respectively. The cell line MER #6 was a gift of S. Schirm and J.M. Bishop. The anti-myc mAb H60C37 was a gift of R. Koski (Amgen). We thank B. Hamilton and M. Palazzolo for helpful suggestions about the cloning approach and J. Rogers for technical assistance during the cloning. We also thank J. Campbell, N. Davidson, P. Mueller, and members of the Wold lab for helpful comments on the manuscript. This work was supported by a grant to B.J.W. from the Margaret Early Trust and from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

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August 20, 2023
August 20, 2023