Failure of insulin secreting pancreatic islet ? cells is a hallmark of both type1 and type 2 diabetes, leading to this laboratory's intense focus on molecular mechanisms regulating pancreatic ? cell development and function. We previously identified Pcif1 in a yeast two hybrid screen for partners of Pdx1, a homeodomain transcription factor and human diabetes gene pivotally positioned in the transcriptional hierarchy governing the development of ? cell mass, the function and survival of adult ? cells, and the ability of adult ? cells to compensate for increased metabolic demand imposed by insulin resistance. During the previous funding period we determined that Pcif1 acts at least in part through its role as a substrate adaptor to recruit Pdx1 into a cullin3-based complex for ubiquitination and proteasomal degradation, thereby implicating Pcif1 as a target for regulating Pdx1 levels. Indeed, Pcif1 loss of function in ? cells elevates Pdx1 protein and stimulates expression of important Pdx1 transcriptional targets, including insulin, MafA and Glut2. In vivo genetic disruption of Pcif1 reveals roles in regulating adult ? cell turnover and function and in endocrine lineage allocation during embryonic development, through Pdx1-dependent and, likely, Pdx1-independent mechanisms. We hypothesize that Pcif1 critically regulates embryonic ? cell formation and the adult ? cell cycle through its ability to modulate the levels/functions of key transcriptional regulators. This hypothesis will be tested in two aims:
Aim 1. To determine how Pcif1 regulates the turnover of adult ? cells, and Aim 2. To determine how Pcif1 influences the emergence of the ? cell lineage during embryonic pancreas development. Insights gained from the proposed experiments will provide a conceptual scaffold for the development of targeted therapeutics that interfere with Pcif1 expression or its interactions with critical substrates in the ? cell to influence ? cell mass and ? cell function, with potential application to approaches involving stem cell differentiation to ? cells, cellular reprogramming of ? cells from other mature cell types, and for approaches to promote the function and regeneration of endogenous beta cell mass in patients with diabetes.
Failure of insulin secreting pancreatic islet ? cells is a hallmark of both type1 and type 2 diabetes, prompting intense effort to develop new sources of insulin- producing ? cells for replacement therapies and new ways to promote endogenous ? cell regeneration. The proposed studies will address important questions about the functions of the ubiquitin ligase substrate adaptor Pcif1 in ? cell biology. Insights gained will provide a conceptual scaffold for the development of targeted therapeutics that interfere with Pcif1 expression or its interactions with critical substrates in the ? cell to influence ? cell mass and ? cell function, with potential application to stem cell differentiation, cellular reprogramming and approaches to promote the function and regeneration of endogenous ? cell mass in patients with diabetes.
|Henley, Kathryn D; Stanescu, Diana E; Kropp, Peter A et al. (2016) Threshold-Dependent Cooperativity of Pdx1 and Oc1 in Pancreatic Progenitors Establishes Competency for Endocrine Differentiation and Î²-Cell Function. Cell Rep 15:2637-50|
|Raum, Jeffrey C; Soleimanpour, Scott A; Groff, David N et al. (2015) Tshz1 Regulates Pancreatic Î²-Cell Maturation. Diabetes 64:2905-14|
|Ediger, Benjamin N; Du, Aiping; Liu, Jingxuan et al. (2014) Islet-1 Is essential for pancreatic Î²-cell function. Diabetes 63:4206-17|
|Liew, Chong Wee; Assmann, Anke; Templin, Andrew T et al. (2014) Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic Î² cells. Proc Natl Acad Sci U S A 111:E2319-28|
|Cannon, Corey E; Titchenell, Paul M; Groff, David N et al. (2014) The Polycomb protein, Bmi1, regulates insulin sensitivity. Mol Metab 3:794-802|
|Khoo, Cynthia; Yang, Juxiang; Weinrott, Samuel A et al. (2012) Research resource: the pdx1 cistrome of pancreatic islets. Mol Endocrinol 26:521-33|
|Claiborn, Kathryn C; Sachdeva, Mira M; Cannon, Corey E et al. (2010) Pcif1 modulates Pdx1 protein stability and pancreatic Ã½Ã½ cell function and survival in mice. J Clin Invest 120:3713-21|
|Yang, Yuqing; Gurung, Buddha; Wu, Ting et al. (2010) Reversal of preexisting hyperglycemia in diabetic mice by acute deletion of the Men1 gene. Proc Natl Acad Sci U S A 107:20358-63|
|Liu, Jiangying; Wang, You; Birnbaum, Morris J et al. (2010) Three-amino-acid-loop-extension homeodomain factor Meis3 regulates cell survival via PDK1. Proc Natl Acad Sci U S A 107:20494-9|
|Sachdeva, Mira M; Stoffers, Doris A (2009) Minireview: Meeting the demand for insulin: molecular mechanisms of adaptive postnatal beta-cell mass expansion. Mol Endocrinol 23:747-58|
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