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Alternative splice variants of the mitochondrial fission protein DNM1L/Drp1 regulate mitochondrial dynamics and tumor progression in ovarian cancer.
Javed, Zaineb; Shin, Dong Hui; Pan, Weihua; White, Sierra R; Kim, Yeon Soo; Elhaw, Amal Taher; Kamlapurkar, Shriya; Cheng, Ya-Yun; Benson, J Cory; Abdelnaby, Ahmed Emam; Phaëton, Rébécca; Wang, Hong-Gang; Yang, Shengyu; Sullivan, Mara L G; St Croix, Claudette M; Watkins, Simon C; Mullett, Steven J; Gelhaus, Stacy L; Lee, Nam; Coffman, Lan G; Aird, Katherine M; Trebak, Mohamed; Mythreye, Karthikeyan; Walter, Vonn; Hempel, Nadine.
Afiliación
  • Javed Z; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, PA, USA.
  • Shin DH; Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, PA, USA.
  • Pan W; Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA.
  • White SR; Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA.
  • Kim YS; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, PA, USA.
  • Elhaw AT; Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, PA, USA.
  • Kamlapurkar S; Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, PA, USA.
  • Cheng YY; Vascular Medicine Institute (VMI), University of Pittsburgh School of Medicine, PA, USA.
  • Benson JC; Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA.
  • Abdelnaby AE; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, PA, USA.
  • Phaëton R; Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, PA, USA.
  • Wang HG; Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA.
  • Yang S; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, PA, USA.
  • Sullivan MLG; Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, PA, USA.
  • St Croix CM; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, PA, USA.
  • Watkins SC; Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, PA, USA.
  • Mullett SJ; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA, USA.
  • Gelhaus SL; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA, USA.
  • Lee N; Department of Obstetrics & Gynecology, College of Medicine, Pennsylvania State University, Hershey, PA, USA.
  • Coffman LG; Department of Pediatrics, College of Medicine, Pennsylvania State University, Hershey, PA, USA.
  • Aird KM; Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, PA, USA.
  • Trebak M; Center for Biologic Imaging, University of Pittsburgh School of Medicine, PA, USA; Division of Pharmacology, Chemistry and Biochemistry, College of Medicine, University of Arizona, Tucson, AZ, USA.
  • Mythreye K; Center for Biologic Imaging, University of Pittsburgh School of Medicine, PA, USA; Division of Pharmacology, Chemistry and Biochemistry, College of Medicine, University of Arizona, Tucson, AZ, USA.
  • Walter V; Center for Biologic Imaging, University of Pittsburgh School of Medicine, PA, USA; Division of Pharmacology, Chemistry and Biochemistry, College of Medicine, University of Arizona, Tucson, AZ, USA.
  • Hempel N; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA, USA.
bioRxiv ; 2024 Jan 24.
Article en En | MEDLINE | ID: mdl-37790404
Aberrant mitochondrial fission/fusion dynamics have been reported in cancer cells. While post translational modifications are known regulators of the mitochondrial fission/fusion machinery, we show that alternative splice variants of the fission protein Drp1 (DNM1L) have specific and unique roles in cancer, adding to the complexity of mitochondrial fission/fusion regulation in tumor cells. Ovarian cancer specimens express an alternative splice transcript variant of Drp1 lacking exon 16 of the variable domain, and high expression of this splice variant relative to other transcripts is associated with poor patient outcome. Unlike the full-length variant, expression of Drp1 lacking exon 16 leads to decreased association of Drp1 to mitochondrial fission sites, more fused mitochondrial networks, enhanced respiration, and TCA cycle metabolites, and is associated with a more metastatic phenotype in vitro and in vivo. These pro-tumorigenic effects can also be inhibited by specific siRNA-mediated inhibition of the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the significance of the pathophysiological consequences of Drp1 alternative splicing and divergent functions of Drp1 splice variants, and strongly warrant consideration of Drp1 splicing in future studies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos