title: RABL6A promotes G1-S phase progression and pancreatic neuroendocrine tumor cell proliferation in an Rb1-dependent manner.
abstract: Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood, and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs (PNET) that correlated with high-level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor-suppressor pathways in the arrested cells. Loss of p53 had no effect on the RABL6A knockdown phenotype, indicating that RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation partially restored G1 to S phase progression in RABL6A-knockdown cells, although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a novel negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients.
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, Iowa.
authors.forename: Jussara
authors.initials: J
authors.lastname: Hagen
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, Iowa. Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, Iowa.
authors.forename: Viviane P
authors.initials: VP
authors.lastname: Muniz
authors.affiliation: Medical Scientist Training Program, University of Iowa, Iowa City, Iowa.
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Falls
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, Iowa. Medical Scientist Training Program, University of Iowa, Iowa City, Iowa.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Reed
authors.affiliation: Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Agshin F
authors.initials: AF
authors.lastname: Taghiyev
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Quelle
authors.affiliation: Department of Microbiology, College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Francoise A
authors.initials: FA
authors.lastname: Gourronc
authors.affiliation: Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Microbiology, College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Aloysius J
authors.initials: AJ
authors.lastname: Klingelhutz
authors.affiliation: Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Major
authors.affiliation: Department of Pathology, College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Askeland
authors.affiliation: Department of Surgery, College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Sherman
authors.affiliation: The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Internal Medicine, College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: O'Dorisio
authors.affiliation: The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Pathology, College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Bellizzi
authors.affiliation: The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Surgery, College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: James R
authors.initials: JR
authors.lastname: Howe
authors.affiliation: Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Darbro
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, Iowa. Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, Iowa. Medical Scientist Training Program, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Pathology, College of Medicine, University of Iowa, Iowa City, Iowa. dawn-quelle@uiowa.edu.
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Quelle
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016193:G1 Phase; D006801:Humans; D008938:Mitosis; D018358:Neuroendocrine Tumors / Q000473:pathology*; D015513:Oncogene Proteins / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000502:physiology*; D016196:S Phase; D020691:rab GTP-Binding Proteins / Q000502:physiology*
chemical_list: D015513:Oncogene Proteins; D016160:Retinoblastoma Protein; C000595658:RABL6A protein, human; D020691:rab GTP-Binding Proteins