WAF1/CIP1 Is Induced in p53-mediated G1 Arrest and Apoptosis

El-Deiry, Wafik S.; Harper, J. Wade; O'Connor, Patrick M.; Velculescu, Victor E.; Canman, Christine E.; Jackman, Joany; Pietenpol, Jennifer A.; Burrell, Marilee; Hill, David E.; Wang, Yisong; Wiman, Klas G.; Mercer, W. Edward; Kastan, Michael B.; Kohn, Kurt W.; Elledge, Stephen J.; Kinzler, Kenneth W.; Vogelstein, Bert

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Articles| March 01 1994

WAF1/CIP1 Is Induced in p53-mediated G₁ Arrest and Apoptosis^¹

Wafik S. El-Deiry;

Wafik S. El-Deiry

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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J. Wade Harper;

J. Wade Harper

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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Patrick M. O'Connor;

Patrick M. O'Connor

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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Victor E. Velculescu;

Victor E. Velculescu

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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Christine E. Canman;

Christine E. Canman

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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Joany Jackman;

Joany Jackman

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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Jennifer A. Pietenpol;

Jennifer A. Pietenpol

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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Marilee Burrell;

Marilee Burrell

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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David E. Hill;

David E. Hill

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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Yisong Wang;

Yisong Wang

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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Klas G. Wiman;

Klas G. Wiman

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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W. Edward Mercer;

W. Edward Mercer

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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Michael B. Kastan;

Michael B. Kastan

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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Kurt W. Kohn;

Kurt W. Kohn

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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Stephen J. Elledge;

Stephen J. Elledge

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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Kenneth W. Kinzler;

Kenneth W. Kinzler

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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Bert Vogelstein

The

Oncology Center and Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine

Baltimore, Maryland 21231 [W. S. E-D., V. E. V., C. E. C., J. A. P., M. B. K., K. W. Ki., B. V.]

The

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH

Bethesda, Maryland 20892 [P. M. O., J. J., K. W. Ko.]

Oncogene Science, Inc.

Cambridge, Massachussetts 02142 [M. B., D. E. H.]

Department of Tumor Biology, Karolinska Institutet

Box 60400, S-104 01, Stockholm, Sweden [K. G. W., Y. W.]

;

Howard Hughes Medical Institute [S. J. E.] and Verna and Marrs McLean Department of Biochemistry and Institute of Molecular Genetics [J. W. H., S. J. E.], Baylor College of Medicine

Houston, Texas 77030

; and

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University

Philadelphia, Pennsylvania 19107 [W. E. M.]

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Author & Article Information

Received: December 28 1993

Accepted: January 20 1994

Online Issn: 1538-7445

Print Issn: 0008-5472

1994

American Association for Cancer Research, Inc.

Cancer Res (1994) 54 (5): 1169–1174.

Abstract

The tumor growth suppressor WAF1/CIP1 was recently shown to be induced by p53 and to be a potent inhibitor of cyclin-dependent kinases. In the present studies, we sought to determine the relationship between the expression of WAF1/CIP1 and endogenous regulation of p53 function. WAF1/CIP1 protein was first localized to the nucleus of cells containing wild-type p53 and undergoing G₁ arrest. WAF1/CIP1 was induced in wild-type p53-containing cells by exposure to DNA damaging agents, but not in mutant p53-containing cells. The induction of WAF1/CIP1 protein occurred in cells undergoing either p53-associated G₁ arrest or apoptosis but not in cells induced to arrest in G₁ or to undergo apoptosis through p53-independent mechanisms. DNA damage led to increased levels of WAF1/CIP1 in cyclin E-containing complexes and to an associated decrease in cyclin-dependent kinase activity. These results support the idea that WAF1/CIP1 is a critical downstream effector in the p53-specific pathway of growth control in mammalian cells.

This work was supported by the Preuss Foundation, the Clayton Fund, the National Foundation for Cancer Research, the Glaxo Research Institute, Inc. (M. B. K. and C. E. C.), the Council for Tobacco Research (M. B. K. and C. E. C.), and NIH Grants GM07309, GM07184, ES05777 (M. B. K.), CA-09071, CA-55541 (W. E. M.), AG-11085 (S. J. E., and J. W. H.), and CA-43460. B. V. is an American Cancer Society research professor.

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1994

American Association for Cancer Research, Inc.

WAF1/CIP1 Is Induced in p53-mediated G₁ Arrest and Apoptosis^¹

Abstract

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WAF1/CIP1 Is Induced in p53-mediated G1 Arrest and Apoptosis1

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WAF1/CIP1 Is Induced in p53-mediated G₁ Arrest and Apoptosis^¹