Reciprocal inhibition of PIN1 and APC/C CDH1 controls timely G1/S transition and creates therapeutic vulnerability.

Autor: Ke S; Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; These authors contributed equally to this work., Dang F; Department of Pathology, Beth Israel Deaconess Medical Center and Cancer Research Institute, Harvard Medical School, Boston, MA 02215, USA.; These authors contributed equally to this work., Wang L; Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; These authors contributed equally to this work., Chen JY; Department of Systems Biology, Harvard Medical School, Boston, MA 02215, USA.; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02215, USA.; These authors contributed equally to this work., Naik MT; Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI 02912, USA., Thavamani A; Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA., Liu Y; Yale Cancer Biology Institute, West Haven, CT 06516, USA.; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510., Li W; Yale Cancer Biology Institute, West Haven, CT 06516, USA., Kim N; Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA., Naik NM; Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI 02912, USA., Sui H; Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen 361023, China., Tang W; Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, USA., Qiu C; Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Koikawa K; Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA., Batalini F; Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Department of Medicine, Division of Medical Oncology, Mayo Clinic, Arizona, USA., Wang X; Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA., Clohessy JG; Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA., Heng YJ; Department of Pathology, Beth Israel Deaconess Medical Center and Cancer Research Institute, Harvard Medical School, Boston, MA 02215, USA., Lahav G; Department of Systems Biology, Harvard Medical School, Boston, MA 02215, USA., Gray NS; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA., Zho XZ; Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Departments of Biochemistry & Oncology, Schulich School of Medicine and Dentistry, and Robarts Research Institute, Western University, London, ON N6A 3K7, Canada., Wei W; Department of Pathology, Beth Israel Deaconess Medical Center and Cancer Research Institute, Harvard Medical School, Boston, MA 02215, USA., Wulf GM; Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA., Lu KP; Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Departments of Biochemistry & Oncology, Schulich School of Medicine and Dentistry, and Robarts Research Institute, Western University, London, ON N6A 3K7, Canada.; Lead Contact.
Jazyk: angličtina
Zdroj: Research square [Res Sq] 2023 Jan 19. Date of Electronic Publication: 2023 Jan 19.
DOI: 10.21203/rs.3.rs-2447544/v1
Abstrakt: Cyclin-dependent kinases (CDKs) mediated phosphorylation inactivates the anaphase-promoting complex (APC/C CDH1 ), an E3 ubiquitin ligase that contains the co-activator CDH1, to promote G1/S transition. PIN1 is a phosphorylation-directed proline isomerase and a master cancer signaling regulator. However, little are known about APC/C CDH1 regulation after phosphorylation and about PIN1 ubiquitin ligases. Here we uncover a domain-oriented reciprocal inhibition that controls the timely G1/S transition: The non-phosphorylated APC/C CDH1 E3 ligase targets PIN1 for degradation in G1 phase, restraining G1/S transition; APC/C CDH1 itself, after phosphorylation by CDKs, is inactivated by PIN1-catalyzed isomerization, promoting G1/S transition. In cancer, PIN1 overexpression and APC/C CDH1 inactivation reinforce each other to promote uncontrolled proliferation and tumorigenesis. Importantly, combined PIN1- and CDK4/6-inhibition reactivates APC/C CDH1 resulting in PIN1 degradation and an insurmountable G1 arrest that translates into synergistic anti-tumor activity against triple-negative breast cancer in vivo. Reciprocal inhibition of PIN1 and APC/C CDH1 is a novel mechanism to control timely G1/S transition that can be harnessed for synergistic anti-cancer therapy.
Databáze: MEDLINE