title: Squamous Cell Carcinoma-related Oncogene (SCCRO) Family Members Regulate Cell Growth and Proliferation through Their Cooperative and Antagonistic Effects on Cullin Neddylation.
abstract: SCCRO (squamous cell carcinoma-related oncogene; also known as DCUN1D1) is a highly conserved gene that functions as an E3 in neddylation. Although inactivation of SCCRO in yeast results in lethality, SCCRO(-/-) mice are viable. The exclusive presence of highly conserved paralogues in higher organisms led us to assess whether compensation by SCCRO paralogues rescues lethality in SCCRO(-/-) mice. Using murine and Drosophila models, we assessed the in vivo activities of SCCRO and its paralogues in cullin neddylation. We found that SCCRO family members have overlapping and antagonistic activity that regulates neddylation and cell proliferation activities in vivo. In flies, both dSCCRO and dSCCRO3 promote neddylation and cell proliferation, whereas dSCCRO4 negatively regulates these processes. Analysis of somatic clones showed that the effects that these paralogues have on proliferation serve to promote cell competition, leading to apoptosis in clones with a net decrease in neddylation activity. We found that dSCCRO and, to a lesser extent, dSCCRO3 rescue the neddylation and proliferation defects promoted by expression of SCCRO4. dSCCRO and dSCCRO3 functioned cooperatively, with their coexpression resulting in an increase in both the neddylated cullin fraction and proliferation activity. In contrast, human SCCRO and SCCRO4 promote, and human SCCRO3 inhibits, neddylation and proliferation when expressed in flies. Our findings provide the first insights into the mechanisms through which SCCRO family members cooperatively regulate neddylation and cell proliferation.
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Weimin
authors.initials: W
authors.lastname: Fu
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Joanne
authors.initials: J
authors.lastname: Sun
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Guochang
authors.initials: G
authors.lastname: Huang
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Liu
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kaufman
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Russell J H
authors.initials: RJ
authors.lastname: Ryan
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Suresh Y
authors.initials: SY
authors.lastname: Ramanathan
authors.affiliation: Department of Biology, The City College of New York, New York, New York 10031.
authors.forename: Tadmiri
authors.initials: T
authors.lastname: Venkatesh
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and singhb@mskcc.org.
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Singh
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D044842:Cullin Proteins / Q000378:metabolism*; D029721:Drosophila Proteins / Q000502:physiology; D004331:Drosophila melanogaster; D005260:Female; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D018345:Mice, Knockout; D009928:Organ Specificity; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000502:physiology*
chemical_list: D044842:Cullin Proteins; C558615:DCUN1D1 protein, mouse; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins
keywords: head and neck cancer; lung cancer; oncogene; tumor suppressor gene; ubiquitylation (ubiquitination)