The DOI matches its Crossref record; 61 of the 62 references it cites were found in a registry or an index.
Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α
Open accessAbstract
The failure to expand functional pancreatic β-cell mass in response to increased metabolic demand is a hallmark of type 2 diabetes. Lineage tracing studies indicate that replication of existing β-cells is the principle mechanism for β-cell expansion in adult mice. Here we demonstrate that the proliferative response of β-cells is dependent on the orphan nuclear receptor hepatocyte nuclear factor-4 α ( HNF-4 α), the gene that is mutated in Maturity-Onset Diabetes of the Young 1 (MODY1). Computational analysis of microarray expression profiles from isolated islets of mice lacking HNF-4 α in pancreatic β-cells reveals that HNF-4α regulates selected genes in the β-cell, many of which are involved in proliferation. Using a physiological model of β-cell expansion, we show that HNF-4 α is required for β-cell replication and the activation of the Ras/ERK signaling cascade in islets. This phenotype correlates with the down-regulation of suppression of tumorigenicity 5 ( ST5 ) in HNF-4 α mutants, which we identify as a novel regulator of ERK phosphorylation in β-cells and a direct transcriptional target of HNF-4α in vivo. Together, these results indicate that HNF-4α is essential for the physiological expansion of adult β-cell mass in response to increased metabolic demand.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Our work also suggests that Mapk/Erk regulation links Pdgfr activation to Ezh2 induction and β-cell proliferation, consistent with studies demonstrating Erk regulation of Ezh2 in cancer cells33, and Erk activation that accompanies mouse β-cell expansion in pregnancy34.”
From PDGF signalling controls age-dependent proliferation in pancreatic β-cells (2011) · cites this paper as [34]
In the citing paper
“Additionally, a recent study showed that the orphan nuclear receptor hepatocyte nuclear factor-4 (HNF-4)α is required in β-cells for the proliferative response of pregnancy through activation of the Ras/ERK signaling cascade, at least in part through the regulation of the guanine nucleotide exchange factor ST5 (Figure 3) [55].”
From Expansion of β-cell mass in response to pregnancy (2010) · cites this paper as [55]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
In silico prediction of protein-protein interactions in human macrophages
Souiai, O., Guerfali, F. Z., Miled, S. B., Brun, C., & Benkahla, A. (2014) · BMC Research Notes · doi:10.1186/1756-0500-7-157 · Cited by 10,785
Significance analysis of microarrays applied to the ionizing radiation response
Tusher, V. G., Tibshirani, R., & Chu, G. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.091062498 · Cited by 10,568
Global and societal implications of the diabetes epidemic
Zimmet, P., Alberti, K. G. M. M., & Shaw, J. (2001) · Nature · doi:10.1038/414782a · Cited by 5,883
Yang, Y., Dudoit, S., Luu, P., Lin, D., Peng, V., Ngai, J., & Speed, T. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.4.e15 · Cited by 3,722
Organoid Models and Applications in Biomedical Research
Xinaris, C., Brizi, V., & Remuzzi, G. (2015) · The Nephron journals/Nephron journals · doi:10.1159/000433566 · Cited by 3,519
Transcriptional Regulatory Networks in Saccharomyces cerevisiae
Lee, T. I., Rinaldi, N. J., Robert, F., Odom, D. T., Bar-Joseph, Z., Gerber, G. K., Hannett, N. M., Harbison, C. T., Thompson, C. M., Simon, I., et al. (2002) · Science · doi:10.1126/science.1075090 · Cited by 2,956
Elective induction versus spontaneous labor after sonographic diagnosis of fetal macrosomia.
Combs, C. A., Singh, N. B., & Khoury, J. C. (1993) · PubMed · Cited by 2,463
Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation
Dor, Y., Brown, J., Martinez, O. I., & Melton, D. A. (2004) · Nature · doi:10.1038/nature02520 · Cited by 2,219
Buchanan, T. A., & Xiang, A. H. (2005) · Journal of Clinical Investigation · doi:10.1172/jci200524531 · Cited by 2,123
Identifying biological themes within lists of genes with EASE
Hosack, D. A., Dennis, G., Sherman, B. T., Lane, H. C., & Lempicki, R. A. (2003) · Genome biology · doi:10.1186/gb-2003-4-10-r70 · Cited by 1,961
Insulin-promoter-factor 1 is required for pancreas development in mice
Jonsson, J., Carlsson, L., Edlund, T., & Edlund, H. (1994) · Nature · doi:10.1038/371606a0 · Cited by 1,879
Genome-Wide Location and Function of DNA Binding Proteins
Ren, B., Robert, F., Wyrick, J. J., Aparicio, O. M., Jennings, E. G., Simon, I., Zeitlinger, J., Schreiber, J., Hannett, N. M., Kanin, E. I., et al. (2000) · Science · doi:10.1126/science.290.5500.2306 · Cited by 1,768
Combinatorial Control of Gene Expression by Nuclear Receptors and Coregulators
McKenna, N. J., & O'Malley, B. W. (2002) · Cell · doi:10.1016/s0092-8674(02)00641-4 · Cited by 1,463
Control of Pancreas and Liver Gene Expression by HNF Transcription Factors
Odom, D. T., Zizlsperger, N., Gordon, D. B., Bell, G. W., Rinaldi, N. J., Murray, H. L., Volkert, T. L., Schreiber, J., Rolfe, A., Gifford, D. K., et al. (2004) · Science · doi:10.1126/science.1089769 · Cited by 1,348
Opening of Compacted Chromatin by Early Developmental Transcription Factors HNF3 (FoxA) and GATA-4
Cirillo, L. A., Lin, F. R., Cuesta, I., Friedman, D., Jarník, M., & Zaret, K. S. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00459-8 · Cited by 1,188
Hayhurst, G. P., Lee, Y.-H., Lambert, G., Ward, J. M., & Gonzalez, F. J. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.4.1393-1403.2001 · Cited by 1,107
p16INK4a induces an age-dependent decline in islet regenerative potential
Krishnamurthy, J., Ramsey, M. R., Ligon, K. L., Torrice, C., Koh, A., Bonner-Weir, S., & Sharpless, N. E. (2006) · Nature · doi:10.1038/nature05092 · Cited by 1,003
Ahlgren, U., Jönsson, J., Jönsson, L., Simu, K., & Edlund, H. (1998) · Genes & Development · doi:10.1101/gad.12.12.1763 · Cited by 918
RefSeq and LocusLink: NCBI gene-centered resources
Pruitt, K. D. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.1.137 · Cited by 884
Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model
Finegood, D. T., Scaglia, L., & Bonner‐Weir, S. (1995) · Diabetes · doi:10.2337/diab.44.3.249 · Cited by 631
Glucagon-like Peptide-1 Receptor Signaling Modulates β Cell Apoptosis
Li, Y., Hansotia, T., Yusta, B., Ris, F., Halban, P. A., & Drucker, D. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209423200 · Cited by 589
Parviz, F., Matullo, C., Garrison, W. D., Savatski, L., Adamson, J. W., Ning, G., Kaestner, K. H., Rossi, J. M., Zaret, K. S., & Duncan, S. A. (2003) · Nature Genetics · doi:10.1038/ng1175 · Cited by 588
Self-citationRegulatory phases of early liver development: paradigms of organogenesis
Zaret, K. S. (2002) · Nature Reviews Genetics · doi:10.1038/nrg837 · Cited by 516
Parsons, J. A. (1992) · Endocrinology · doi:10.1210/en.130.3.1459 · Cited by 476
Calcineurin/NFAT signalling regulates pancreatic β-cell growth and function
Heit, J. J., Apelqvist, Å., Gu, X., Winslow, M. M., Neilson, J. R., Crabtree, G. R., & Kim, S. K. (2006) · Nature · doi:10.1038/nature05097 · Cited by 445
Gene expression cascades in pancreatic development
Wilson, M. E., Scheel, D., & German, M. S. (2002) · Mechanisms of Development · doi:10.1016/s0925-4773(02)00333-7 · Cited by 354
Increased islet apoptosis in Pdx1+/- mice.
Johnson, J. D., Ahmed, N. T., Luciani, D., Han, Z.-Q., Tran, H. D., Fujita, J., Misler, S., Edlund, H., & Polonsky, K. (2003) · Journal of Clinical Investigation · doi:10.1172/jci16537 · Cited by 348
Kulkarni, R., Jhala, U. S., Winnay, J. N., Krajewski, S., Montminy, M., & Kahn, C. R. (2004) · Journal of Clinical Investigation · doi:10.1172/jci21845 · Cited by 263
Glucocorticoid Receptor-Dependent Gene Regulatory Networks
Le, P. P., Friedman, J. R., Schug, J., Brestelli, J. E., Parker, J. B., Bochkis, I. M., & Kaestner, K. H. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0010016 · Cited by 252
Self-citationMGD: the Mouse Genome Database
Blake, J. A. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg047 · Cited by 246
The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion
Gupta, R. K., Vatamaniuk, M. Z., Lee, C. S., Flaschen, R. C., Fulmer, J. T., Matschinsky, F. M., Duncan, S. A., & Kaestner, K. H. (2005) · Journal of Clinical Investigation · doi:10.1172/jci22365 · Cited by 239
Self-citationZaret, K. (1999) · Developmental Biology · doi:10.1006/dbio.1999.9228 · Cited by 209
Ellard, S., Beards, F., Allen, L. I. S., Shepherd, M. H., Ballantyne, E., Harvey, R., & Hattersley, A. T. (2000) · Diabetologia · doi:10.1007/s001250050038 · Cited by 207
Wang, H.-Y., Maechler, P., Antinozzi, P., Hagenfeldt, K., & Wollheim, C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m006612200 · Cited by 200
Foxa2 regulates multiple pathways of insulin secretion
Lantz, K. A., Vatamaniuk, M. Z., Brestelli, J. E., Friedman, J. R., Matschinsky, F. M., & Kaestner, K. H. (2004) · Journal of Clinical Investigation · doi:10.1172/jci21149 · Cited by 171
Self-citationMiura, A., Yamagata, K., Kakei, M., Hatakeyama, H., Takahashi, N. K., Fukui, K., Nammo, T., Yoneda, K., Inoue, Y., Sladek, F. M., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507496200 · Cited by 163
Wang, H.-Y., Maechler, P., Hagenfeldt, K., & Wollheim, C. (1998) · EMBO Journal · doi:10.1093/emboj/17.22.6701 · Cited by 162
The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation
Fukui, K., Yang, Q., Cao, Y., Takahashi, N. K., Hatakeyama, H., Wang, H., Wada, J., Zhang, Y., Marselli, L., Nammo, T., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.11.003 · Cited by 152
The FoxM1 Transcription Factor Is Required to Maintain Pancreatic β-Cell Mass
Zhang, H., Ackermann, A. M., Gusarova, G. A., Lowe, D., Xue, F., Kopsombut, G., Costa, R. H., & GANNON, M. A. (2006) · Molecular Endocrinology · doi:10.1210/me.2006-0056 · Cited by 142
Identification of Transcriptional Networks during Liver Regeneration
White, P., Brestelli, J. E., Kaestner, K. H., & Greenbaum, L. E. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m410844200 · Cited by 120
Self-citationAmaral, M. E. C., Cunha, D. A., Anhê, G. F., Ueno, M., Carneiro, E. M., Velloso, L. A., Bordin, S., & Boschero, A. C. (2004) · Journal of Endocrinology · doi:10.1677/joe.1.05547 · Cited by 110
Weng, J., Ekelund, M., Lehto, M. J., Li, H., Ekberg, G., Frid, A. H., Åberg, A., Groop, L., & Berntorp, K. E. (2002) · Diabetes Care · doi:10.2337/diacare.25.1.68 · Cited by 96
Ras‐GRF1 signaling is required for normal β‐cell development and glucose homeostasis
de Mora, J. F., Esteban, L. M., Burks, D. J., Núñez, A., Garcés, C., García‐Barrado, M. J., Osma, M. D. C. I., Moratinos, J., Ward, J. M., & Santos, E. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg280 · Cited by 93
Functional Genomics of the Endocrine Pancreas
Scearce, L. M., Brestelli, J. E., McWeeney, S. K., Lee, C. S., Mazzarelli, J. M., Pinney, D. F., Pizarro, A., Stoeckert, C. J., Clifton, S. W., Permutt, M. A., et al. (2002) · Diabetes · doi:10.2337/diabetes.51.7.1997 · Cited by 78
Self-citationLu, Y., Herrera, P. L., Guo, Y., Sun, D. F., Tang, Z., LeRoith, D., & Liu, J. (2004) · Diabetes · doi:10.2337/diabetes.53.12.3131 · Cited by 73
Hagenfeldt-Johansson, K. A., Herrera, P. L., Wang, H., Gjinovci, A., Ishihara, H., & Wollheim, C. B. (2001) · Endocrinology · doi:10.1210/endo.142.12.8592 · Cited by 72
Molecular etiologies of mody and other early-onset forms of diabetes
Shih, D. Q., & Stoffel, M. (2002) · Current Diabetes Reports · doi:10.1007/s11892-002-0071-9 · Cited by 68
Wang, L., Coffinier, C., Thomas, M. K., Gresh, L., Eddu, G., Manor, T., Levitsky, L. L., Yaniv, M., & Rhoads, D. B. (2004) · Endocrinology · doi:10.1210/en.2004-0281 · Cited by 65
(2003) · Hormone and Metabolic Research · doi:10.1055/s-2003-41303 · Cited by 61
In vivo role of the HNF4α AF‐1 activation domain revealed by exon swapping
Briançon, N., & Weiss, M. C. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601021 · Cited by 59
Transcriptional Program of the Endocrine Pancreas in Mice and Humans
Kaestner, K. H., Lee, C. S., Scearce, L. M., Brestelli, J. E., Arsenlis, A., Le, P. P., Lantz, K. A., Crabtree, J., Pizarro, A., Mazzarelli, J. M., et al. (2003) · Diabetes · doi:10.2337/diabetes.52.7.1604 · Cited by 59
Self-citationRachdi, L., Balcázar, N., Elghazi, L., Barker, D. J., Krits, I., Kiyokawa, H., & Bernal‐Mizrachi, E. (2006) · Diabetes · doi:10.2337/db06-0861 · Cited by 51
Orthogonal analysis of C/EBPβ targets in vivo during liver proliferation
Friedman, J. R., Larris, B., Le, P. P., Peiris, T. H., Arsenlis, A., Schug, J., Tobias, J. W., Kaestner, K. H., & Greenbaum, L. E. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402875101 · Cited by 49
Self-citationManduchi, E., Grant, G. R., He, H., Liu, J., Mailman, M. D., Pizarro, A., Whetzel, P. L., & Stoeckert, C. J. (2004) · Bioinformatics · doi:10.1093/bioinformatics/btg428 · Cited by 45
Self-citationRubins, N. E., Friedman, J. R., Le, P. P., Zhang, L., Brestelli, J. E., & Kaestner, K. H. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.16.7069-7077.2005 · Cited by 44
Self-citationActivation of Extracellular Signal-regulated Kinase 2 by a Novel Abl-binding Protein, ST5
Majidi, M., Hubbs, A. E., & Lichy, J. H. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.26.16608 · Cited by 32
Burns, C. J., Squires, P. E., & Persaud, S. J. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2179 · Cited by 29
Lichy, J. H. (1996) · Nucleic Acids Research · doi:10.1093/nar/24.23.4700 · Cited by 23
Hagenfeldt-Johansson, K. A. (2001) · Endocrinology · doi:10.1210/en.142.12.5311 · Cited by 16
Zhu, Y., King, B. L., Parvizi, B., Brunk, B. P., Stoeckert, C. J., Quackenbush, J. F., Richardson, J. E., & Bult, C. J. (2003) · Genome biology · doi:10.1186/gb-2003-4-2-r16 · Cited by 16
Self-citation
Cited by
Sorted by citations
Recovery from diabetes in mice by β cell regeneration
Nir, T., Melton, D. A., & Dor, Y. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32959 · Cited by 595
Expansion of β-cell mass in response to pregnancy
Rieck, S., & Kaestner, K. H. (2010) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2009.11.001 · Cited by 358
Self-citationOrnoy, A., Becker, M., Weinstein‐Fudim, L., & Ergaz, Z. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062965 · Cited by 377
Sandovici, I., Smith, N. H., Nitert, M. D., Ackers-Johnson, M., Uribe-Lewis, S., Ito, Y., Jones, R. H., Marquez, V. E., Cairns, W., Tadayyon, M., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019007108 · Cited by 326
MicroRNAs Control Intestinal Epithelial Differentiation, Architecture, and Barrier Function
McKenna, L. B., Schug, J., Vourekas, A., McKenna, J., Bramswig, N. C., Friedman, J. R., & Kaestner, K. H. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.07.040 · Cited by 320
Self-citation
Metadata
- Authors
- Gupta, R. K., Gao, N., Gorski, R. K., White, P., Hardy, O. T., Rafiq, K., Brestelli, J. E., Chen, G., Stoeckert, C. J., & Kaestner, K. H.
- Affiliations
- University of Pennsylvania (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-04-01
- Volume
- 21
- Issue
- 7
- Pages
- 756-769
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1838528
- OpenAlex
- W2158386353
- Cited by
- 161
- References
- 62
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 9 · 2020: 4 · 2019: 5 · 2018: 6 · 2017: 6 · 2016: 6 · 2015: 9 · 2014: 9 · 2013: 17 · 2012: 10
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pennsylvania (NIH DK19525)
- National Institutes of Health (DK 19525)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 19525, DK-56947, R24DK056947, DK-55342, R01DK055342, U01DK056947, P30DK019525)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- HNF4α, beta-cell proliferation, type 2 diabetes, MODY1, ST5, Ras/ERK signaling, ERK1/2 phosphorylation, orphan nuclear receptor, transcriptional regulation, metabolic demand, islets
- MeSH terms
- Animals, Base Sequence, DNA-Binding Proteins, Female, Islets of Langerhans, Mice, Transgenic, Models, Genetic, Molecular Sequence Data, Pregnancy, Transcription, Genetic, Signal Transduction, ras Proteins, Tumor Suppressor Proteins, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, Insulin-Secreting Cells, Mice, Hepatocyte Nuclear Factor 4
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
