Michael Kastan

Overview:

Dr. Kastan earned his M.D./Ph.D. from Washington University School of Medicine and did his clinical training in Pediatrics and Pediatric Hematology-Oncology at Johns Hopkins. He was a Professor of Oncology at Johns Hopkins prior to becoming Chair of the Hematology-Oncology Department and later Cancer Center Director at St. Jude Children’s Research Hospital, before moving to Duke in 2011, where he currently serves as the Executive Director of the Duke Cancer Institute and is the William and Jane Shingleton Professor of Pharmacology and Cancer Biology. His laboratory research has focused on cellular responses to DNA damage, including many highly cited publications reporting the roles of p53 and ATM in DNA damage signaling. Among his numerous honors are election to the National Academy of Sciences, National Academy of Medicine, and the American Academy of Arts and Sciences, and receipt of the AACR-G.H.A. Clowes Memorial Award and Failla Award from the Radiation Research Society. He has served as Chair of the Board of Scientific Counselors of the National Cancer Institute (NCI), on the Boards of Directors of the American Association for Cancer Research (AACR) and the American Association of Cancer Institutes (AACI), and as Editor-in-Chief of the journal Molecular Cancer Research. His lab continues to study molecular and biochemical controls of cellular stress responses, particularly those related to DNA damage, and has spun out two companies focused on novel anti-cancer therapeutics.

Positions:

William and Jane Shingleton Distinguished Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Director of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Professor of Pediatrics

Pediatrics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1984

Washington University in St. Louis

Ph.D. 1984

Washington University in St. Louis

Grants:

Using bacterial CRISPR/Cas endonucleases to selectively eliminate HPV-transformed cells in vivo

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Development and Validation of Novel Therapeutic Targets in Anal Cancer

Administered By
Medicine, Medical Oncology
Awarded By
The Farrah Fawcett Foundation
Role
Collaborator
Start Date
End Date

The role of ATM in Metabolic Stress Responses

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

The role of ATM in Metabolic Stress Responses

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Metabolic Sensing and Stress Response Deficit in Ataxia Telangiectasia

Administered By
Pharmacology & Cancer Biology
Awarded By
A-T Children's Project
Role
Principal Investigator
Start Date
End Date

Publications:

Participation of ATM, SMG1, and DDX5 in a DNA Damage-Induced Alternative Splicing Pathway.

Altered cellular responses to DNA damage can contribute to cancer development, progression, and therapeutic resistance. Mutations in key DNA damage response factors occur across many cancer types, and the DNA damage-responsive gene, TP53, is frequently mutated in a high percentage of cancers. We recently reported that an alternative splicing pathway induced by DNA damage regulates alternative splicing of TP53 RNA and further modulates cellular stress responses. Through damage-induced inhibition of the SMG1 kinase, TP53 pre-mRNA is alternatively spliced to generate TP53b mRNA and p53b protein is required for optimal induction of cellular senescence after ionizing radiation-induced DNA damage. Herein, we confirmed and extended these observations by demonstrating that the ATM protein kinase is required for repression of SMG1 kinase activity after ionizing radiation. We found that the RNA helicase and splicing factor, DDX5, interacts with SMG1, is required for alternative splicing of TP53 pre-mRNA to TP53b and TP53c mRNAs after DNA damage, and contributes to radiation-induced cellular senescence. Interestingly, the role of SMG1 in alternative splicing of p53 appears to be distinguishable from its role in regulating nonsense-mediated RNA decay. Thus, ATM, SMG1, and DDX5 participate in a DNA damage-induced alternative splicing pathway that regulates TP53 splicing and modulates radiation-induced cellular senescence.
Authors
McCann, JJ; Fleenor, DE; Chen, J; Lai, C-H; Bass, TE; Kastan, MB
MLA Citation
McCann, Jennifer J., et al. “Participation of ATM, SMG1, and DDX5 in a DNA Damage-Induced Alternative Splicing Pathway.Radiat Res, vol. 199, no. 4, Apr. 2023, pp. 406–21. Pubmed, doi:10.1667/RADE-22-00219.1.
URI
https://scholars.duke.edu/individual/pub1569233
PMID
36921295
Source
pubmed
Published In
Radiat Res
Volume
199
Published Date
Start Page
406
End Page
421
DOI
10.1667/RADE-22-00219.1

ATM Regulation of the Cohesin Complex Is Required for Repression of DNA Replication and Transcription in the Vicinity of DNA Double-Strand Breaks.

Multiple members of the cohesin complex are involved in the regulation of DNA replication and transcription in the vicinity of DNA double-strand breaks and their role(s) are regulated by the ATM kinase.
Authors
Bass, TE; Fleenor, DE; Burrell, PE; Kastan, MB
MLA Citation
Bass, Thomas E., et al. “ATM Regulation of the Cohesin Complex Is Required for Repression of DNA Replication and Transcription in the Vicinity of DNA Double-Strand Breaks.Mol Cancer Res, vol. 21, no. 3, Mar. 2023, pp. 261–73. Pubmed, doi:10.1158/1541-7786.MCR-22-0399.
URI
https://scholars.duke.edu/individual/pub1559401
PMID
36469004
Source
pubmed
Published In
Mol Cancer Res
Volume
21
Published Date
Start Page
261
End Page
273
DOI
10.1158/1541-7786.MCR-22-0399

Abeloff’s Clinical Oncology

Easily accessible and clinically focused, Abeloff’s Clinical Oncology, 6th Edition, covers recent advances in our understanding of the pathophysiology of cancer, cellular and molecular causes of cancer initiation and progression, new and emerging therapies, current trials, and much more. Masterfully authored by an international team of leading cancer experts, it offers clear, practical coverage of everything from basic science to multidisciplinary collaboration on diagnosis, staging, treatment and follow up.
Authors
Niederhuber, JE; Armitage, JO; Doroshow, JH; Kastan, MB; Tepper, JE
MLA Citation
Niederhuber, J. E., et al. Abeloff’s Clinical Oncology. 2019, pp. 1–2037. Scopus, doi:10.1016/B978-0-323-47674-4.00124-9.
URI
https://scholars.duke.edu/individual/pub1509808
Source
scopus
Published Date
Start Page
1
End Page
2037
DOI
10.1016/B978-0-323-47674-4.00124-9

Preface

Authors
Niederhuber, JE; Armitage, JO; Doroshow, JH; Kastan, MB; Tepper, JE
MLA Citation
Niederhuber, J. E., et al. Preface. 2019, pp. xxvii–xxvii. Scopus, doi:10.1016/B978-0-323-47674-4.00129-8.
URI
https://scholars.duke.edu/individual/pub1509809
Source
scopus
Published Date
Start Page
xxvii
End Page
xxvii
DOI
10.1016/B978-0-323-47674-4.00129-8

DNA Damage Response Pathways and Cancer

DNA repair and the cellular response to DNA damage are critical for maintaining genomic stability. Defects in DNA repair or the response to DNA damage encountered from endogenous or external sources results in an increased rate of genetic mutations, often leading to the development of cancer. Inherited mutations in DNA damage response pathway genes often result in cancer susceptibility. The major active pathways for DNA repair in humans are nucleotide excision repair, base excision repair, mismatch DNA repair, translesional DNA synthesis, and homologous recombination or nonhomologous end joining processes for double-strand break repair.
Authors
Ford, JM; Kastan, MB
MLA Citation
Ford, J. M., and M. B. Kastan. “DNA Damage Response Pathways and Cancer.” Abeloff’s Clinical Oncology, 2019, pp. 154-164.e4. Scopus, doi:10.1016/B978-0-323-47674-4.00011-6.
URI
https://scholars.duke.edu/individual/pub1509810
Source
scopus
Published Date
Start Page
154
End Page
164.e4
DOI
10.1016/B978-0-323-47674-4.00011-6