Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic β cells
Open accessAbstract
Diabetes results from an inadequate mass of functional beta cells, due to either beta cell loss caused by immune assault or the lack of compensation to overcome insulin resistance. Elucidating the mechanisms that regulate beta cell mass has important ramifications for fostering beta cell regeneration and the treatment of diabetes. We report here that Skp2, a substrate recognition component of Skp1-Cul1-F-box (SCF) ubiquitin ligase, played an essential and specific role in regulating the cellular abundance of p27 and was a critical determinant of beta cell proliferation. In Skp2(-/-) mice, accumulation of p27 resulted in enlarged polyploid beta cells as a result of endoreduplication replacing proliferation. Despite beta cell hypertrophy, Skp2(-/-) mice exhibited diminished beta cell mass, hypoinsulinemia, and glucose intolerance. Increased insulin resistance resulting from diet-induced obesity caused Skp2(-/-) mice to become overtly diabetic, because beta cell growth in the absence of cell division was insufficient to compensate for increased metabolic demand. These results indicate that the Skp2-mediated degradation pathway regulating the cellular degradation of p27 is essential for establishing beta cell mass and to respond to increased metabolic demand associated with insulin resistance.
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Other known Foxm1 targets such as Skp2 have been implicated in β-cell compensation in response to diet-induced obesity.
“Other known Foxm1 targets such as Skp2 have already been implicated in β-cell compensation in response to diet-induced obesity [65], and the proliferative response of the β-cell to pregnancy in mice is dependent on Foxm1 itself [66].”
From Expansion of β-cell mass in response to pregnancy (2010) · cites this paper as [65]
Proliferation of β-cells appears to play an important role in endogenous renewal.
“The cell source and mechanism leading to the endogenous renewal is not clear, although proliferation of β-cells appears to play an important role (11).”
From Age-Dependent Decline in β-Cell Proliferation Restricts the Capacity of β-Cell Regeneration in Mice (2009) · cites this paper as [11]
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Multiscale Light Field Microscopy Platform for Multi-purpose Dynamic Volumetric BioimagingPreprint
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Self-citationDevelopment of a novel peripherally acting alpha2A-adrenergic receptor antagonist for anti-diabeticPreprint
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- Authors
- Zhong, L., Georgia, S., Tschen, S.-I., Nakayama, K., Nakayama, K., & Bhushan, A.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Bhushan, Anil
- Venue
- Journal of Clinical Investigation
- Published
- 2007-10-01
- Volume
- 117
- Issue
- 10
- Pages
- 2869-2876
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1964513
- OpenAlex
- W2163493623
- Cited by
- 92
- References
- 37
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 1 · 2016: 10 · 2015: 5 · 2014: 9 · 2013: 8 · 2012: 6
- FWCI
- 8.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Center for AIDS Research, University of Washington
- National Institute of General Medical Sciences (T32GM007185)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK068763)
- Jonsson Comprehensive Cancer Center
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- Skp2, p27 degradation, pancreatic beta cells, beta-cell mass, beta-cell proliferation, endoreduplication, polyploidy, SCF ubiquitin ligase, insulin resistance, diet-induced obesity, diabetes mellitus, impaired glucose tolerance, hypoinsulinemia, beta cell regeneration
- MeSH terms
- Animals, Glucose, Insulin, Insulin Resistance, Mice, Mutant Strains, Polyploidy, Gene Deletion, S-Phase Kinase-Associated Proteins, Cell Proliferation, Insulin-Secreting Cells, Cyclin-Dependent Kinase Inhibitor p27, Mice
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