[Frontiers in Bioscience, 3, d250-268, February 15, 1998] 250 MYC AND THE CELL CYCLE Bruno Amati, Konstantinos Alevizopoulos and Jaromir Vlach Swiss Institute for Experimental Cancer Research (ISREC), CH-1066 Epalinges, Switzerland Received 1/28/98 Accepted 2/11/98 TABLE OF CONTENTS 1. Abstract 2. Introduction 2.1. The Myc protein 2.2. G1-S control in mammalian cells: an outline 3. Myc positively regulates CDK function through several pathways 3.1. Myc antagonizes the function of p27Kip1 3.1.1. Constitutive expression of Myc prevents p27-induced growth arrest 3.1.2. Activation of Myc induces cell cycle entry by suppressing p27 function 3.2. Myc up-regulates cyclin E expression, but what is the mechanism? 3.3. Myc target genes and cell cycle control: cdc25A may be one, others are still missing 3.4. The effects of decreasing or increasing Myc activity in growing cells 4. Myc and the p16-pRb pathway 4.1. Cyclin E, the spy who came in from the cold 4.2. Cellular context may determine the ability of Myc to promote cell cycle progression 4.3. Relationship between Myc and cyclin D1 in mitogenic signalling 5. Myc as a downstream target of pocket proteins and E2F 6. Lessons from a Myc knock-out cell line: independent effects on cell cycle and cell growth 7. Cellular transformation and Oncogene cooperation: the example of Myc and Ras 7.1. Myc and Ras: interplay in cell cycle control 7.2. Interplay between tumor suppressor and oncogenic pathways 7.3. Do p21, p27 or p57 function as tumor suppressors? 8. Perspectives 9. Acknowledgments 10. References 1. ABSTRACT Ectopic expression of the c-Myc oncoprotein prevents cell cycle arrest in response to growth-inhibitory signals, differentiation stimuli, or mitogen withdrawal. Moreover, Myc activation in quiescent cells is sufficient to induce cell cycle entry in the absence of growth factors. Thus, Myc transduces a potent mitogenic stimulus but, concomitantly, induces apoptosis in the absence of survival factors. We review here recent progress in our understanding of the molecular mechanisms linking Myc activity to cell cycle control. Myc is a positive regulator of G1-specific cyclin-dependent kinases (CDKs) and, in particular, of cyclin E/CDK2 complexes. Cyclin D/CDK4 and CDK6 may conceivably also be activated by Myc, but the circumstances in which this occurs remain to be explored. Myc acts via at least three distinct pathways which can enhance CDK function: (1) functional inactivation of the CDK inhibitor p27 Kip1 and probably also of p21 Cip1 and p57 Kip2 , (2) induction of the CDK-activating phosphatase Cdc25A and (3) - in an ill understood and most likely indirect way - deregulation of cyclin E expression. Constitutive expression of either Myc or cyclin E can prevent growth arrest by p16 INK4a (an inhibitor of cyclin D/CDK4, but not of cyclin E/CDK2). In cells, p16 INK4a inhibits phosphorylation, and thus induces activation of the Retinoblastoma-family proteins (pRb, p107 and p130). Surprisingly, this effect of p16 is not altered in the presence of Myc or cyclin E. Thus, Myc and cyclin E/CDK2 activity unlink activation of p16 and pRb from growth arrest. Finally, Myc may itself be a functional target of cyclin D/CDK4 through its direct interaction with p107. We discuss how the effects of Myc on cell cycle control may relate to its oncogenic activity, and in particular to its ability to cooperate with activated Ras oncoproteins. 2. INTRODUCTION 2.1. The Myc protein The myc family of proto-Oncogenes includes three evolutionarily conserved genes c-, N- and L-myc, which encode related proteins. Oncogenic activation of myc genes generally results in their constitutive expression, and contributes to progression of a wide range of human and animal neoplasias (reviewed in 1-3). myc genes are differentially expressed during embryonic development (e.g. 4). With few exceptions, proliferating post-natal tissues express c-myc (reviewed in 1). c-myc expression is strictly dependent on mitogenic signals, is suppressed by growth- inhibitory signals and inducers of differentiation, and is important for proliferation and apoptosis in response to the appropriate stimuli (reviewed in 1, 2). The c-Myc protein (or Myc) conveys itself strong mitogenic and apoptotic stimuli.