Squamous Cell Carcinoma-related Oncogene (SCCRO) Family Members Regulate Cell Growth and Proliferation through Their Cooperative and Antagonistic Effects on Cullin Neddylation.

Authors

• Weimin Fu
• Joanne Sun
• Guochang Huang
• Jeffrey C Liu
• Andrew Kaufman
• Russell J H Ryan
• Suresh Y Ramanathan
• Tadmiri Venkatesh
• Bhuvanesh Singh

Publication/Presentation Date

3-18-2016

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.

Volume

291

Issue

12

First Page

6200

Last Page

6217

ISSN

1083-351X

Published In/Presented At

Fu, W., Sun, J., Huang, G., Liu, J. C., Kaufman, A., Ryan, R. J., Ramanathan, S. Y., Venkatesh, T., & Singh, B. (2016). Squamous Cell Carcinoma-related Oncogene (SCCRO) Family Members Regulate Cell Growth and Proliferation through Their Cooperative and Antagonistic Effects on Cullin Neddylation. The Journal of biological chemistry, 291(12), 6200–6217. https://doi.org/10.1074/jbc.M115.692756

Disciplines

Medicine and Health Sciences

PubMedID

26792857

Department(s)

Department of Surgery

Document Type

Article