Norbert Berndt

Childrens Hospital Los Angeles, USC School of Medicine, Los Angeles, CA 90027

TABLE OF CONTENTS

1. Abstract

2. Introduction

3. The Context

3.1. Protein Phosphatase 1 as a Multifunctional Enzyme

3.1.1. Small Molecular Weight Inhibitors of Protein Phosphatases
3.1.2. Protein Phosphatase 1 Isozymes
3.1.3. Regulatory Subunits of PP1

3.2. Cell Cycle Regulation — As we Know it

3.2.1. The Significance of G1 Regulation for the Organism
3.2.2. The Role of Post-translational Modification in Cell Cycle Control

4. The Cell Cycle from a Phosphatase’s Point of View

4.1. Mitotic Entry and Exit
4.2. The G1/S Transition
4.3. Apoptosis — Another Way of Exiting the Cell Cycle
4.4. A Model for the Regulation and Function of PP1

5. Perspectives

5.1. Transformation and Tumor Progression
5.2. Other Phosphatases and other Processes Related to Growth Control

6. Summary

7. Acknowledgments

8. References

1. ABSTRACT

Regulating the cell number is critically important for the development and maintenance of a multi-cellular organism. The cell number can be altered by inducing cell proliferation and/or programmed cell death (apoptosis). These two processes are linked by cell cycle-regulatory pathways, and protein phosphorylation and proteolytic degradation play key roles in both. Protein dephosphorylation has been a rather neglected aspect of cell cycle control. Recent advances in this field make it imperative to provide a view of the cell cycle from a phosphatase’s vantage point. Although a number of protein phosphatases may be instrumental in cell cycle and apoptosis control, the emphasis here will be on the prototypical Ser/Thr-specific protein phosphatase PP1. Experiments will be considered in their historical context. The major goal of this review will be to re-evaluate the hypothesis that PP1 — and other protein phosphatases — may function as negative growth regulators. Currently available evidence suggests that PP1 activity is required for exit from mitosis, yet may also block cell cycle progression and facilitate apoptosis. Where appropriate, results highlighting the role of the other major phosphatase, PP2A, will also be discussed. This review will conclude with some unresolved issues including the question whether PP1 might be a suitable target for anti-cancer strategies.