Marcos Malumbres - Centro Nacional de Investigaciones Oncológica (CNIO).
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El miércoles 27 de septiembre del 2017 organizamos en la Fundación Ramón Areces un Simposio Internacional sobre nuevas perspectivas en la investigación sobre el cáncer. En colaboración con el Centro Nacional de Investigaciones Oncológicas (CNIO) y Weizmann Institute for Science.
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Marcos Malumbres - Centro Nacional de Investigaciones Oncológica (CNIO).
- 1. P-Plk1 a-tub DAPI P The Cell Division Cycle Mechanims and Implications in Disease M. Malumbres Spanish National Cancer Research Centre (CNIO)
- 2. The Cell Division Cycle
- 3. Plk1 is a cell cycle (Ser/Thr) kinase involved in centrosome maturation, chromosome attachment and cytokinesis Plk1 in the Cell Division Cycle
- 4. Plk1 inhibition Mol Cancer Ther 2006;5(4) Plk1 inhibitors DMSO Plk1 inhibition leads to mitotic arrest and cell death in vitro and in vivo
- 5. Volasertib (BI6727), “Breakthroug h Therapy” designation by the FDA in acute myeloid leukemia (AML) Plk1 inhibitors in Clinical Trials
- 6. What is the physiological role of Plk1 at the organism level?
- 7. ATG TGA Plk1(lox) 1 2 3 4 5 6 7 8 9 10 ATG TGA Plk1(loxfrt) 1 2 3 4 5 6 7 8 9 10 neo ATG TGA Plk1(–) 1 3 4 5 6 7 8 9 10 Flp Cre Plk1 mouse models pCMV rtTA TRE - pCMV Flag-Plk1 cDNA Rosa26 rtTA Collagen locus cDNA integration DOX ON - OFF low - HIGH Loss-of-fuction Gain-of-fuction
- 8. Plk1(+/+) Plk1(–/–) Plk1(–/–) a-tub DAPI a-tub DAPI Plk1(+/+) Plk1(–/–) ACA Embryonic lethality in Plk1-null embryos
- 9. Plk1 is essential for mitosis in vivo
- 10. Plk1 heterozygous mice Plk1(+/-) mice display: abnormal brain development Increased brain volume Plk1 is regulates asymmetric cell división in neural progenitor cells
- 11. Plk1 heterozygous mice Plk1(+/-) mice display: abnormal brain development cardiovascular defects Age (months) Plk1(+/+) Plk1(+/–) Plk1(+/–) ♀ Plk1(+/–) ♂ Survival (%) (from cardiovascular death) ** 0 6 12 18 24 40 60 80 100 ** **
- 12. Plk1 heterozygous mice Plk1(+/-) mice display: abnormal brain development cardiovascular defects Plk1(+/–) Plk1(+/+)
- 13. Abnormal structure of arterias in Plk1(+/-) mice AS DIA SR Structural alterations in the arterial elastic layer & lost of elasticity Increase internal diameter in arteries & aneurisms
- 14. Plk1 is induced upon hypertension
- 15. (Plk1_lox) X (SM22a-CreERT2) Specific ablation of Plk1 in Smooth Muscle Cells Plk1 (lox/lox) (D/D)SM lox D M - H A H A - TMX + TMX (H) - heart (A) - aorta Specific ablation in arterias Hypotension
- 16. Specific ablation of Plk1 in Smooth Muscle Cells 10 weeks old Angiotensin II Deficient contraction Protected from hypertension
- 17. Lack of contraction of actomyosin fibers Smooth muscle cells isolated from mutant mice Actomyosin contraction is a RhoA-dependent process
- 18. Plk1 re-localizes to contraction areas
- 19. Plk1 inhibitors prevent vascular funcion
- 20. Plk1 inhibitors induce breaks in the aorta And cooperate with hypertension (AngII) in inducing vascular defects
- 21. Plk1 inhibitors induce breaks and aneurisms AngII + DMSO AngII + Volasertib H&E EVG de Carcer et al. Nat Med 2017
- 22. Molecular mechanism? Plk1 phosphorylated a RhoA- GAP and recruits Ect2, a RhoA Exchange factor RhoA ROCK MLC Plk1MYPT1 VASOCONSTRICTORS VASCULAR CONTRACTION ECT2 RacGap1 p115-GEF aPKC
- 24. A conserved mechanism in Plk1 function Plk1 RhoA Cytokinesis Blood pressure PLk1 Contraction
- 25. A syndrome with Plk1 haploinsufficiency Ballif et al. (2007) Nat. Genet. 39:107 PLK1 Skull phenotype − Head circumference − Flat face − Frontal bossing − Short nose with wide nasal bridge Psychomotor and Cognitive delay Cardiovasular disease
- 26. Take-Home messages Plk1 is a major regulator of RhoA activity during acto-myosin contraction: a conserved function from yeast to mammals a conserved function from proliferating to differentiated cells not only in cytokinesis: also during contraction of arterias Mouse models provide a unique system to understand the physiological relevance of proteins; hopefully before their inhibitors reach the Clinic Arteria function and structure should be monitored during therapeutic treatments with volasertib against cancer (e.g. AML)
- 27. Mónica Alvarez- Fernández Guillermo de Cárcer Aisha El-Bakali José González-Martínez Begoña Hurtado Carolina Maestre María Maroto Diego Martínez-Alonso Anna F. B. Martins Marianna Trakala María Salazar-Roa Belén Sanz María Sanz Flores Elisabet Zapatero X. Bustelo, M.A. Sevilla, M.J. Montero (CIC, Univ. Salamanca) S. Martínez-Martínez, J. Oller, N. Méndez-Barbero, J.M. Redondo (CNIC) Cell Division and Cancer Group Spanish National Cancer Research Centre (CNIO)