. 2024 Apr 15;15(1):3220.

doi: 10.1038/s41467-024-47427-w.

Reciprocal antagonism of PIN1-APC/C^CDH1 governs mitotic protein stability and cell cycle entry

Shizhong Ke^#¹, Fabin Dang^#², Lin Wang^#¹, Jia-Yun Chen^#^{3

4}, Mandar T Naik⁵, Wenxue Li⁶, Abhishek Thavamani¹, Nami Kim¹, Nandita M Naik⁵, Huaxiu Sui⁷, Wei Tang⁸, Chenxi Qiu^{1

9}, Kazuhiro Koikawa¹, Felipe Batalini^{1

10}, Emily Stern Gatof¹, Daniela Arango Isaza¹, Jaymin M Patel¹, Xiaodong Wang¹¹, John G Clohessy¹², Yujing J Heng², Galit Lahav³, Yansheng Liu^{6

13}, Nathanael S Gray¹⁴, Xiao Zhen Zhou¹⁵, Wenyi Wei¹⁶, Gerburg M Wulf¹⁷, Kun Ping Lu¹⁸

Affiliations

¹ Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
² Department of Pathology, Beth Israel Deaconess Medical Center and Cancer Research Institute, Harvard Medical School, Boston, MA, 02215, USA.
³ Department of Systems Biology, Harvard Medical School, Boston, MA, 02215, USA.
⁴ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02215, USA.
⁵ Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI, 02912, USA.
⁶ Yale Cancer Biology Institute, West Haven, CT, 06516, USA.
⁷ Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, 361023, China.
⁸ Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, MD, USA.
⁹ Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
¹⁰ Department of Medicine, Division of Medical Oncology, Mayo Clinic, Phoenix, AZ, USA.
¹¹ Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02215, USA.
¹² Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
¹³ Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06510, USA.
¹⁴ Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University, Stanford, CA, 94305, USA.
¹⁵ Departments of Pathology and Laboratory Medicine, Biochemistry, and Oncology, and Lawson Health Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 3K7, Canada. xzhou659@uwo.ca.
¹⁶ Department of Pathology, Beth Israel Deaconess Medical Center and Cancer Research Institute, Harvard Medical School, Boston, MA, 02215, USA. wwei2@bidmc.harvard.edu.
¹⁷ Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. gwulf@bidmc.harvard.edu.
¹⁸ Departments of Biochemistry and Oncology, and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 3K7, Canada. klu92@uwo.ca.

^# Contributed equally.

PMID: 38622115
PMCID: PMC11018817
DOI: 10.1038/s41467-024-47427-w

Reciprocal antagonism of PIN1-APC/C^CDH1 governs mitotic protein stability and cell cycle entry

Shizhong Ke et al. Nat Commun. 2024.

. 2024 Apr 15;15(1):3220.

doi: 10.1038/s41467-024-47427-w.

Authors

Affiliations

¹ Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
² Department of Pathology, Beth Israel Deaconess Medical Center and Cancer Research Institute, Harvard Medical School, Boston, MA, 02215, USA.
³ Department of Systems Biology, Harvard Medical School, Boston, MA, 02215, USA.
⁴ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02215, USA.
⁵ Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI, 02912, USA.
⁶ Yale Cancer Biology Institute, West Haven, CT, 06516, USA.
⁷ Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, 361023, China.
⁸ Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, MD, USA.
⁹ Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
¹⁰ Department of Medicine, Division of Medical Oncology, Mayo Clinic, Phoenix, AZ, USA.
¹¹ Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02215, USA.
¹² Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
¹³ Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06510, USA.
¹⁴ Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University, Stanford, CA, 94305, USA.
¹⁵ Departments of Pathology and Laboratory Medicine, Biochemistry, and Oncology, and Lawson Health Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 3K7, Canada. xzhou659@uwo.ca.
¹⁶ Department of Pathology, Beth Israel Deaconess Medical Center and Cancer Research Institute, Harvard Medical School, Boston, MA, 02215, USA. wwei2@bidmc.harvard.edu.
¹⁷ Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. gwulf@bidmc.harvard.edu.
¹⁸ Departments of Biochemistry and Oncology, and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 3K7, Canada. klu92@uwo.ca.

^# Contributed equally.

PMID: 38622115
PMCID: PMC11018817
DOI: 10.1038/s41467-024-47427-w

Abstract

Induced oncoproteins degradation provides an attractive anti-cancer modality. Activation of anaphase-promoting complex (APC/C^CDH1) prevents cell-cycle entry by targeting crucial mitotic proteins for degradation. Phosphorylation of its co-activator CDH1 modulates the E3 ligase activity, but little is known about its regulation after phosphorylation and how to effectively harness APC/C^CDH1 activity to treat cancer. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1)-catalyzed phosphorylation-dependent cis-trans prolyl isomerization drives tumor malignancy. However, the mechanisms controlling its protein turnover remain elusive. Through proteomic screens and structural characterizations, we identify a reciprocal antagonism of PIN1-APC/C^CDH1 mediated by domain-oriented phosphorylation-dependent dual interactions as a fundamental mechanism governing mitotic protein stability and cell-cycle entry. Remarkably, combined PIN1 and cyclin-dependent protein kinases (CDKs) inhibition creates a positive feedback loop of PIN1 inhibition and APC/C^CDH1 activation to irreversibly degrade PIN1 and other crucial mitotic proteins, which force permanent cell-cycle exit and trigger anti-tumor immunity, translating into synergistic efficacy against triple-negative breast cancer.

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Conflict of interest statement

S.K., G.M.W., N.S.G., X.Z.Z., and K.P.L. are inventors of several issued patents and/or pending patent applications on PIN1, PIN1 biomarkers, PIN1 inhibitors and PIN1 inhibitor combination to treat human diseases; X.Z.Z. and K.P.L. are the scientific founders and former scientific advisors of and own equity in Pinteon. Their interests were reviewed and managed by BIDMC in accordance with its conflict-of-interest policy. G.M.W. reports research funding from Glaxo Smith Kline (institutional funding). W.W. is a co-founder and consultant for the Rekindle Therapeutics. N.S.G. is a founder, science advisory board member (SAB) and equity holder in Syros, C4, Allorion, Lighthorse, Inception, Voronoi, Matchpoint, Shenandoah (board member), Larkspur (board member) and Soltego (board member). The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Arbella, Deerfield and Sanofi. All other authors do not have any competing interests.

Figures

**Fig. 1. Cell cycle regulator APC/C^CDH1 is a physiological E3 ligase for PIN1.**
a Overall survival for BC with low and high PIN1 protein abundance in Tang et al. dataset. PIN1-Low, n = 56 patients; PIN1-High, n = 9 patients. b Overall survival for BC with low and high PIN1 protein levels in a TMA slide. PIN1-Low, n = 103 patients; PIN1-High, n = 57 patients. Log rank test, p = 7e-04 (a), p = 0.0235 (b). c Violin plots with overlaid box plots showing PIN1 intensity at the single-cell level in the whole BC tissue specimens grouped into Non-tumors (N), Tumors (T) or Refractory Tumors (RT). Box plots, the central line marks 50th percentile, the box edges indicate the 25th and 75th percentiles, and the whiskers stretch to the minima and maxima within 1.5x the IQR (Inter-Quartile Range) from the quartiles. n > 5000 cells. One-way ANOVA followed by Tukey’s multiple comparisons test. p values are shown. d Venn diagram showing the number of hits obtained from the two IP-MS screens for potential PIN1-related E3 ubiquitin ligases. e Co-IP of endogenous CDH1 with endogenous PIN1. MDA-MB-231 cells (left) and transgenic mouse cells (right) were treated with 10 μM MG132 for 12 hrs and precipitated with IgG or anti-PIN1 antibodies. Input is 5% of the total lysates. f IB analysis of indicated proteins from shCDH1 or shCDC20 MDA-MB-231 and MCF-7 cells treated with increasing concentrations of ATRA (5 μM, 20 μM) for 3 days. g Intensity plots of PIN1 and APC/C reporter in MCF-10A cells synchronized in G1 phase, followed by releasing back into the cell cycle at indicated time points. h Fluorescent intensity of PIN1 and APC/C reporter were quantified and log2 transformed across the time courses. Data in graphs are mean ± SD. i IB analysis of indicated proteins from WT and *CDH1* KO MEFs synchronized in G1 phase by serum starvation, followed by releasing back into the cell cycle at indicated time points. j Cell-cycle profiles corresponding to (i) monitored by flow cytometry. The images were representative images from 3 independent experiments (e, f, i, j). Source data are provided as a Source Data file.

**Fig. 2. Constitutively active APC/C^CDH1 targets PIN1 and other mitotic proteins for degradation to provoke cell cycle exit.**
a Domain architecture of CDH1 highlighting potential phosphorylation sites for CDKs. b Morphology of MCF-7 and MDA-MB-468 cells stably expressing CDH1-7A. c Left, SA-β-gal stain in MDA-MB-231 and SUM-159 cells expressing CDH1-7A. Scale bars, 20 µm. Right, Quantification of SA-β-gal positive cells. n = 3 independent experiments. Data in graphs are mean ± SD and analyzed by unpaired two-sided t-test. EV vs. CDH1-7A, p = 0.0001 (MDA-MB-231), p = 0.0002 (SUM-159). d IB analysis of indicated proteins from 293T cells transfected with Flag-PIN1 and a gradient of CDH1-7A constructs. e IB analysis of ubiquitination of Flag-PIN1 from 293T cells transfected with the indicated constructs for 48 hours and treated with 2 μM MG132 for 12 h and pulled down by Ni-NTA agarose. f In vitro ubiquitination assay using APC/C from cells in G1 phase and recombinant PIN1. E2C/S, E2 enzymes UBE2C and UBE2S. g IB analysis of indicated proteins from MDA-MB-231 or MDA-MB-468 cells stably expressing CDH1-7A and treated with 10 μM MG132 for 12 h. h RT-PCR analysis of indicated mRNA of WT and CDH1-7A MDA-MB-231 and MDA-MB-468 cells. n = 3 independent experiments. Data in graphs are mean ± SD and analyzed by two-way ANOVA followed by Bonferroni’s multiple comparisons test. p values are shown. i GST-PIN1 pull-down precipitates derived from MDA-MB-231 cells stably expressing HA-CDH1 or HA-CDH1-7A, treated with 10 μM MG132 for 12 h. j IB analysis of indicated proteins from MDA-MB-231 cells stably co-expressing CDH1-7A or empty vector (EV) in the presence of Flag-PIN1 and its mutants. k IB analysis of ubiquitination of Flag-PIN1 and its RLAA mutant from 293T cells transfected with the indicated constructs for 48 h and treated with 2 μM MG132 for 12 h and pulled down by Ni-NTA agarose. l Docking model of the interaction between D-box of PIN1 and WD40 domain of CDH1. The images were representative images from 3 independent experiments (b–g, i–k). Source data are provided as a Source Data file.

**Fig. 3. Loss of PIN1 reactivates APC/C^CDH1 and destabilizes mitotic proteins.**
a Long-term colony-formation assay of indicated BC wild-type and *PIN1* KO cell lines. Cells were grown for about 2 weeks, fixed and stained with crystal violet. b Gene Ontology (GO) enrichment analysis was applied to proteomics of *PIN1* KO versus WT MDA-MB-231 cells. Color codes for p-value and symbol size codes for the ratio of proteins related to specific GO term/total number of proteins significantly altered. Data were obtained from Kozono et al. 2018 and analyzed by one-sided hypergeometric test. c IB analysis for indicated proteins derived from WT and *PIN1* KO MDA-MB-231 cells synchronized in M phase by nocodazole and then released back into the cell cycle for the indicated time. d Cell-cycle profiles of WT (blue) and *PIN1* KO (pink) in (c) as determined by FACS. e DNA contents were measured by FACS in WT and *PIN1* KO MDA-MB-231 cells synchronized at the G1/S boundary by double thymidine block and then released back into the cell cycle for 4 h. f Cell cycle phase distribution of WT and *PIN1* KO MDA-MB-231 cells from (e). n = 3 independent experiments. Data in graphs are mean ± SD and analyzed by unpaired two-sided t-test. WT vs. *PIN1*-KO, p = 0.0007 (0 h), p = 0.0006 (4 h). g, Tracking cell division (green square) and cell death (black rhomboid) at the single cell level. Asynchronous cultures of MCF-7 WT and *PIN1* KO cells expressing the APC-degron reporter were followed for 72 h for single cell expression of mCherry-Geminin (shades of blue). h Frequency of G0/G1 arrest (ratio of G0/G1 arrested cells to total cells) in WT and *PIN1* KO MCF-7 cells stably expressing the APC/C-degron reporter from (g). WT, n = 168 cells; *PIN1* KO, n = 191 cells. The error bar indicates 95% confidence interval determined by bootstrapping. i Cycloheximide (CHX) chase assay for indicated proteins derived from WT and *PIN1* KO MDA-MB-468 cells treated with 50 µg/ml CHX for the indicated time. The images were representative images from 3 independent experiments (a, c–e, i). Source data are provided as a Source Data file.

**Fig. 4. PIN1 catalyzes *trans* to *cis* isomerization of the pS163-P motif in CDH1 to prevent CDH1 dephosphorylation.**
a 293T cells were transfected with indicated constructs for 36 hrs. Input is 5% of the total lysates used in IP. b In vitro kinase assay showing that CDK4 phosphorylates CDH1 at Ser163. c FACS analysis of APC/C-degron reporter levels in MCF-7 cells expressing either WT CDH1, S163A or S163E mutants CDH1. d IB analysis of indicated proteins derived from MCF-7 cells expressing either WT CDH1, S163A or S163E mutants CDH1 and treated with 1 μM palbociclib for 3 days. e IB analysis of GST pull-down precipitates derived from 293T cells transfected with GST-PIN1 and HA-CDH1 mutants for 36 h. f NMR analysis of phosphorylated peptide bound to PIN1. Average chemical shift perturbation in PIN1 backbone amide resonances on the binding of the CDH1 phosphopeptide. g Overlay of two-dimensional (2D) ¹H-¹⁵N Heteronuclear single quantum coherence (HSQC) spectrum from the backbone of R17, S18, W34, and E35, and the W34 sidechain of ¹⁵N-labeled PIN1 (blue) and its complex with the CDH1 phosphopeptide (orange). h HADDOCK model demonstrating putative interaction between the CDH1 phosphopeptide shown as red sticks and PIN1 WW (magenta) and PPIase domain (cyan; PDB: 1PIN). i Overlay of ¹³C-HSQC spectra acquired on free peptide (red) and its complex with PIN1 (green). The peak volumes were used to derive isomer population estimates. j DIA-MS analysis of the relative abundance of the peptide containing phosphorylation site of CDH1-S163 derived from WT or *PIN1* KO MCF-7 cells stably expressing HA-CDH1. k IB analysis of indicated immunoprecipitates derived from WT or *PIN1* KO MCF-7 cells expressing either WT CDH1, S163A or S163E mutants CDH1 and pulled down by anti-HA antibody. Input is 5% of the total lysates used in IP. l Schematic diagram illustrating PIN1-catalyzed *trans* to *cis* prolyl-isomerization of the CDH1-pS163-P motif. The images were representative images from 3 independent experiments (a–e, k). Source data are provided as a Source Data file.

**Fig. 5. Pharmacologic inhibition of PIN1 and CDK4 synergistically and irreversibly reactivates APC/C^CDH1 to induce degradation of PIN1 and other mitotic proteins.**
a IB analysis of immunoprecipitates from WT and *PIN1*-KO MDA-MB-231 cells treated with Palbociclib. b Dot plots of FACS for *PIN1*-KO or WT MCF-7 cells stably expressing the APC/C-degron reporter and treated with AApin (1.5 μM ATO + 15 μM ATRA) for 3 days. Dots color, reporter levels. c Tracking cell division and cell death of MCF-7 cells in response to Palbociclib (4 μM), Sulfopin (10 μM) or AApin (1.5 μM ATO + 15 μM ATRA). d Frequency of G0/G1 arrest in MCF-7 cells from (c). n > 90 cells. The error bar indicates 95% confidence interval determined by bootstrapping. Detection of endogenous PIN1-CDH1 (e) and CDK4-CDH1 interactions (f) by PLA in the indicated cells treated with combination of 1 μM Palbociclib and 10 μM Sulfopin for 3 days. Nucleus were stained by DAPI. Scale bars, 5 μm. (Right) Quantification of PLA signals. n > 30 cells. Data are analyzed by unpaired two-sided t-test. p values are shown (d–f). g IB analysis for indicated proteins from WT and *CDH1*-KO MCF-7 cells treated with combination of 1 μM Palbociclib and AApin (ATO (0.5, 1, 1.5, 2 μM) + ATRA (5, 10, 15, 20 μM)) for 3 days. h IB analysis for indicated proteins derived WT and *CDH1*-KO BT-549 cells treated with 5 μM Sulfopin, 2.5 μM Palbociclib or their combination for 3 days. i CHX assay for indicated proteins from WT and *CDH1*-KO MDA-MB-231 cells pre-treated with combination of 10 μM Sulfopin and 1 μM Palbociclib for 36 h followed by 50 µg/ml CHX for the indicated time. j IB analysis of ubiquitinated PIN1 from WT and *CDH1*-KO MDA-MB-231 cells treated with 1 μM Palbociclib and 10 μM Sulfopin for 3 days and 2 μM MG132 for last 12 h and pulled down by Ni-NTA agarose. k, l Schematic diagrams showing the reciprocal inhibition of PIN1-APC/C^CDH1 governs cell-cycle entry and exit. The images were representative images from 3 independent experiments (a, b, e–j). Source data are provided as a Source Data file.

**Fig. 6. PIN1 inhibitors synergize with CDK4 inhibitors against TNBC in human cells and immune-compromised mouse models.**
Colony formation of MDA-MB-231 (a) and SUM-159 cells (b) treated with Sulfopin and Palbociclib for 2 weeks. c IB analysis of PIN1 in SUM-159 cells treated as in (b). d Correlation of cell growth inhibition (b) and PIN1 abundance (c) in SUM-159 cells. Two-sided p value for Pearson correlation coefficient. e Cell counts of MDA-MB-231 cells treated with 1 μM Palbociclib, 10 μM Sulfopin or their combination for 4 days. n = 3 independent experiments. Data in graphs are mean ± SD and analyzed by unpaired two-sided t-test. p values are shown. f MDA-MB-231 cells were treated with increasing concentrations of indicated drugs for 3 days, followed by analyzing apoptotic and necrotic cells by FACS. n = 2 independent experiments. g Tumor growth of TNBC PDOX from different treatments. Data in graphs are mean ± SEM and analyzed by unpaired two-sided t-test. Mice numbers and p values are shown. h Tumor sizes were shown when mice were euthanized after 45 days. NT, no tumor detectable. i Representative immunofluorescence images for PDOX tumors stained with PIN1 (green) and Ki67 (red). Scale bars, 50 µm. j Tumor growth of MDA-MB-468 xenografts from different treatments. k Tumor weights were measured when mice were euthanized after 7 weeks. n = 5 mice per group (j, k). Data in graphs are mean ± SEM and analyzed by unpaired two-sided t-test. p values are shown (j, k). l Representative immunofluorescence images for MDA-MB-468 xenografts tumors stained with PIN1 (green), Ki67 (red) and Geminin (pink). Scale bars, 50 µm. m Growth curves (left) and tumor weights (right) of K14cre; Brca1wt/f; p53wt/f_BT3 tumors from different treatments, n = 6 mice per group. n Growth curves (left) and tumor weights (right) of K14cre; Brca1wt/f; p53wt/f_BT1 tumors from different treatments, n = 5 mice per group. Data in graphs are mean ± SEM and analyzed by unpaired two-sided t-test (m, n). p values are shown (m, n). The images were representative images from 3 independent experiments (a–c). Source data are provided as a Source Data file.

**Fig. 7. Combination of PIN1- and CDK4-inhibitors achieves synergistic anti-tumor immunity and efficacy against RB-proficient or -deficient TNBC in immune-competent mouse models.**
Growth curve (a) and survival curve (b) generated from FVB mice bearing K14cre; Brca1wt/f; p53wt/f_BT3 tumors treated with vehicle (median survival of 18 days), Sulfopin (median survival of 21 days), Palbociclib (median survival of 21 days) or their combination (median survival of 34.5 days), n = 10 mice per group. Growth curve (c) and survival curve (d) generated from FVB mice bearing K14cre; Brca1wt/f; p53wt/f_BT3 tumors treated with vehicle (median survival of 19 days), Sulfopin (median survival of 25 days), Abemaciclib median survival of 25 days) or their combination (median survival of 55 days), n = 10 mice per group. Data are mean ± SEM and analyzed by two-sided unpaired student’s t-test (a, c) or log-rank test (b, d). p values are shown (a–d). e Concatenated UMAP plots displaying 24,000 CD45+ cells derived from K14cre; p53wt/f; Brca1wt/f mouse tumors treated with Sulfopin, Abemaciclib or their combination for two weeks and colored by the main cell populations based on manual annotation of PhenoGraph clustering. f Individual UMAPs for CD45+ cells from different treatments. g–l The violin plots generated by CyTOF data showing percentages of indicated cells from different treatments. n = 7 per group. Data in graphs are analyzed by unpaired two-sided t-test. Vehicle vs. Combination, p values are shown. Source data are provided as a Source Data file.

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References

1. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer. 2009;9:153–166. doi: 10.1038/nrc2602. - DOI - PubMed
1. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov. 2015;14:130–146. doi: 10.1038/nrd4504. - DOI - PMC - PubMed
1. Deshpande A, Sicinski P, Hinds PW. Cyclins and cdks in development and cancer: a perspective. Oncogene. 2005;24:2909–2915. doi: 10.1038/sj.onc.1208618. - DOI - PubMed
1. Maiani E, et al. AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity. Nature. 2021;592:799–803. doi: 10.1038/s41586-021-03422-5. - DOI - PMC - PubMed
1. Simoneschi D, et al. CRL4(AMBRA1) is a master regulator of D-type cyclins. Nature. 2021;592:789–793. doi: 10.1038/s41586-021-03445-y. - DOI - PMC - PubMed

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Reciprocal antagonism of PIN1-APC/C^CDH1 governs mitotic protein stability and cell cycle entry

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Reciprocal antagonism of PIN1-APC/C^CDH1 governs mitotic protein stability and cell cycle entry

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