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

Article navigation

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.]

Search for other works by this author on:

This Site

PubMed

Google Scholar

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.

¹

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.

This content is only available via PDF.

1994

American Association for Cancer Research, Inc.

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

Abstract

See also

commentary

Citing articles via

Email alerts

AACR Journals

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

Abstract

See also

commentary

Citing articles via

Email alerts

AACR Journals

This Feature Is Available To Subscribers Only

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