title: Depletion of PAK1 enhances ubiquitin-mediated survivin degradation in pancreatic β-cells.
abstract: Functional β-cell mass deficiency in diabetes results from imbalanced β-cell death and replication, and decreased PAK1 protein levels in human islets from donors with type 2 diabetes implicates a possible role for PAK1 in maintaining β-cell mass. Here, we aim to address the linkage between PAK1 and Survivin, a protein essential for β-cell replication. PAK1 knockout (KO) mouse islets exhibited decreased expression of Survivin protein. MIN6 β-cells with siRNA-mediated suppression of PAK1 also had decreased Survivin protein and exhibited an increased level of ubiquitinated-Survivin. However, no significant changes in Survivin mRNA were found in islets from PAK1 KO mice and PAK1-depleted MIN6 β-cells. The decreased Survivin level in MIN6 cells subjected to hyperglycemic stress was prevented by expression of exogenous PAK1. Moreover, overexpressing Survivin restored proliferation of β-cells that was impaired by the loss of PAK1. These data implicate a role for PAK1 in regulating Survivin protein stability in the β-cell and suggest PAK1 as a potential molecular target for the restoration of β-cell mass.
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Chen
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Fueger
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D006943:Hyperglycemia / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055550:Protein Stability; D059748:Proteolysis; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D046509:Tissue Culture Techniques; D054875:Ubiquitination; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D012097:Repressor Proteins; D000077022:Survivin; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases
keywords: MIN6; PAK1; Survivin; Ubiquitination; mouse islet; pancreatic β-cell; replication