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.
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|Claiborn, Kathryn C; Sachdeva, Mira M; Cannon, Corey E et al. (2010) Pcif1 modulates Pdx1 protein stability and pancreatic ýý cell function and survival in mice. J Clin Invest 120:3713-21|
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|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|
|Sachdeva, Mira M; Claiborn, Kathryn C; Khoo, Cynthia et al. (2009) Pdx1 (MODY4) regulates pancreatic beta cell susceptibility to ER stress. Proc Natl Acad Sci U S A 106:19090-5|
|Oliver-Krasinski, Jennifer M; Kasner, Margaret T; Yang, Juxiang et al. (2009) The diabetes gene Pdx1 regulates the transcriptional network of pancreatic endocrine progenitor cells in mice. J Clin Invest 119:1888-98|
|Oliver-Krasinski, Jennifer M; Stoffers, Doris A (2008) On the origin of the beta cell. Genes Dev 22:1998-2021|
|Claiborn, Kathryn C; Stoffers, Doris A (2008) Toward a cell-based cure for diabetes: advances in production and transplant of beta cells. Mt Sinai J Med 75:362-71|
|Liu, Aihua; Oliver-Krasinski, Jennifer; Stoffers, Doris A (2006) Two conserved domains in PCIF1 mediate interaction with pancreatic transcription factor PDX-1. FEBS Lett 580:6701-6|
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