Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia
Abstract
To ascertain the role of cyclin-dependent kinase 4 (Cdk4) in vivo, we have targeted the mouse Cdk4 locus by homologous recombination to generate two strains of mice, one that lacks Cdk4 expression and one that expresses a Cdk4 molecule with an activating mutation. Embryonic fibroblasts proliferate normally in the absence of Cdk4 but have a delayed S phase on re-entry into the cell cycle. Moreover, mice devoid of Cdk4 are viable, but small in size and infertile. These mice also develop insulin-deficient diabetes due to a reduction in beta-islet pancreatic cells. In contrast, mice expressing a mutant Cdk4 that cannot bind the cell-cycle inhibitor P16INK4a display pancreatic hyperplasia due to abnormal proliferation of beta-islet cells. These results establish Cdk4 as an essential regulator of specific cell types.
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Inducing cell cycle arrest specifically in β-cells by p27 overexpression or postnatal Cdk4 deletion causes β-cell mass to decrease or fail to expand.
“For instance, when cell cycle arrest is induced specifically in β-cells by overexpression of p27 [24] or by deletion of Cdk4 postnatally, β-cell mass decreases or fails to expand, which would not be the case if neogenesis or transdifferentiation were major sources of new β-cells [25,26].”
From Expansion of β-cell mass in response to pregnancy (2010) · cites this paper as [25]
The tumour suppressor CDKN2A produces p16INK4a, which blocks CDK4, a key controller of pancreatic beta cell replication.
“CDKN2A is a known tumour suppressor and its product, p16INK4a, inhibits CDK4 (cyclin-dependent kinase 4), a powerful regulator of pancreatic beta cell replication (19-21).”
From Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes (2007) · cites this paper as [19]
Predicted side effects of targeted therapy may involve glucose intolerance based on pancreatic β-cell requirements for CDK4 and p16INK4a effects on islet regeneration.
“predicted side effects of targeted therapy may involve glucose intolerance, based on requirements of pancreatic β-cells for CDK4 (85, 86) and effects of p16INK4a on age-dependent islet cell regeneration (87)”
From Targeting CDK4 and CDK6: From Discovery to Therapy (2016) · cites this paper as [85]
Cites
Sherr, C. J. (1996) · Science · doi:10.1126/science.274.5293.1672 · Cited by 5,379 · see citing works
Williams Textbook of Endocrinology
Melmed, S., & Polonsky, K. С. (2016) · Elsevier eBooks · doi:10.1016/c2013-0-15980-6 · Cited by 3,716 · see citing works
Liu, J.-P., Baker, J. C., Perkins, A. S., Robertson, E. J., & Efstratiadis, A. (1993) · Cell · doi:10.1016/s0092-8674(05)80084-4 · Cited by 2,854 · see citing works
Role of insulin-like growth factors in embryonic and postnatal growth
Baker, J., Liu, J.-P., Robertson, E. J., & Efstratiadis, A. (1993) · Cell · doi:10.1016/s0092-8674(05)80085-6 · Cited by 2,463 · see citing works
The regulation of E2F by pRB-family proteins.
Dyson, N. (1998) · Genes & Development · doi:10.1101/gad.12.15.2245 · Cited by 2,317 · see citing works
CYCLIN-DEPENDENT KINASES: Engines, Clocks, and Microprocessors
Morgan, D. O. (1997) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.13.1.261 · Cited by 2,248 · see citing works
Disruption of IRS-2 causes type 2 diabetes in mice
Withers, D., Gutiérrez, J., Towery, H., Burks, D., Ren, J.-M., Previs, S., Zhang, Y., Bernal, D., Pons, S., Shulman, G., et al. (1998) · Nature · doi:10.1038/36116 · Cited by 1,850 · see citing works
DeChiara, T. M., Efstratiadis, A., & Robertsen, E. J. (1990) · Nature · doi:10.1038/345078a0 · Cited by 1,663 · see citing works
Nakayama, K., Ishida, N., Shirane, M., Inomata, A., Inoue, T., SHISHIDO, N., Horii, I., Loh, D. Y., & Nakayama, K. (1996) · Cell · doi:10.1016/s0092-8674(00)81237-4 · Cited by 1,548 · see citing works
Fero, M. L., Rivkin, M. J., Tasch, M., Porter, P. L., Carow, C. E., Firpo, E. J., Polyák, K., Tsai, L., Broudy, V. C., Perlmutter, R. M., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81239-8 · Cited by 1,459 · see citing works
Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene
Tybulewicz, V. L. J., Crawford, C. E., Jackson, P. K., Bronson, R. T., & Mulligan, R. C. (1991) · Cell · doi:10.1016/0092-8674(91)90011-m · Cited by 1,281 · see citing works
Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene
Araki, E., Lipes, M. A., Patti, M.-E., Brüning, J. C., Haag III, B., Johnson, R. S., & Kahn, C. R. (1994) · Nature · doi:10.1038/372186a0 · Cited by 1,252 · see citing works
Enhanced Growth of Mice Lacking the Cyclin-Dependent Kinase Inhibitor Function of p27
Kiyokawa, H., Kineman, R. D., Manova-Todorova, K. O., Soares, V., Hoffman, E. S., Ono, M., Khanam, D., Hayday, A., Frohman, L. A., & Koff, A. (1996) · Cell · doi:10.1016/s0092-8674(00)81238-6 · Cited by 1,243 · see citing works
Williams' Textbook of Endocrinology.
(1991) · Annals of Internal Medicine · doi:10.7326/0003-4819-114-9-816_5 · Cited by 1,156 · see citing works
A p16 INK4a -Insensitive CDK4 Mutant Targeted by Cytolytic T Lymphocytes in a Human Melanoma
Wölfel, T., Hauer, M., Schneider, J., Serrano, M., Wölfel, C., Klehmann, E., Plaen, E. D., Hankeln, T., Büschenfelde, K. M. Z., & Beach, D. (1995) · Science · doi:10.1126/science.7652577 · Cited by 1,153 · see citing works
Graña, X., & Reddy, E. P. (1995) · PubMed · Cited by 1,131 · see citing works
Self-citationInsulin resistance and growth retardation in mice lacking insulin receptor substrate-1
Tamemoto, H., Kadowaki, T., Tobe, K., Yagi, T., Sakura, H., Hayakawa, T., Terauchi, Y., Ueki, K., Kaburagi, Y., Satoh, S., et al. (1994) · Nature · doi:10.1038/372182a0 · Cited by 1,082 · see citing works
Cyclin D1 provides a link between development and oncogenesis in the retina and breast
Sicinski, P., Donaher, J. L., Parker, S. B., Li, T., Fazeli, A., Gardner, H., Haslam, S. Z., Bronson, R. T., Elledge, S. J., & Weinberg, R. A. (1995) · Cell · doi:10.1016/0092-8674(95)90034-9 · Cited by 1,021 · see citing works
Developmental biology of the pancreas
Slack, J. M. W. (1995) · Development · doi:10.1242/dev.121.6.1569 · Cited by 965 · see citing works
Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma
Zuo, L., Weger, J., Yang, Q., Goldstein, A. M., Tucker, M. A., Walker, G. J., Hayward, N., & Dracopoli, N. C. (1996) · Nature Genetics · doi:10.1038/ng0196-97 · Cited by 818 · cited 1× · see citing works
“The importance of the interaction between CDK4 and p16 INK4a became apparent with the identification of a mutation in CDK4 in patients with familial melanom”
BackgroundCyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis
Siciński, P., Donaher, J. L., Geng, Y., Parker, S. B., Gardner, H., Park, M. Y., Robker, R. L., Richards, J. S., McGinnis, L. K., Biggers, J. D., et al. (1996) · Nature · doi:10.1038/384470a0 · Cited by 697 · see citing works
Effects of an Igf1 Gene Null Mutation on Mouse Reproduction
Baker, J., Hardy, M. P., Zhou, J., Bondy, C., Lupu, F., Bellvé, A. R., & Efstratiadis, A. (1996) · Molecular Endocrinology · doi:10.1210/mend.10.7.8813730 · Cited by 674 · see citing works
Hunter, T. R. (1997) · Cell · doi:10.1016/s0092-8674(00)81872-3 · Cited by 552 · see citing works
Development of a Novel Polygenic Model of NIDDM in Mice Heterozygous for IR and IRS-1 Null Alleles
Brüning, J. C., Winnay, J. N., Bonner‐Weir, S., Taylor, S. I., Accili, D., & Kahn, C. R. (1997) · Cell · doi:10.1016/s0092-8674(00)81896-6 · Cited by 545 · see citing works
Role of the cyclin-dependent kinase inhibitors in the development of cancer
Hirama, T., & Koeffler, H. (1995) · Blood · doi:10.1182/blood.v86.3.841.bloodjournal863841 · Cited by 390 · see citing works
Regulation of Expression of Steroidogenic Enzymes in Leydig Cells1
Payne, A. H., & Youngblood, G. L. (1995) · Biology of Reproduction · doi:10.1095/biolreprod52.2.217 · Cited by 343 · see citing works
The retinoblastoma gene family: cousins with overlapping interests
Mulligan, G. (1998) · Trends in Genetics · doi:10.1016/s0168-9525(98)01470-x · Cited by 334 · see citing works
Phenotypic alterations in insulin-deficient mutant mice
Duvillié, B., Cordonnier, N., Deltour, L., Dandoy‐Dron, F., Itier, J., Monthioux, E., Jami, J., Joshi, R. L., & Bucchini, D. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.5137 · Cited by 272 · see citing works
Diabetic Hyperglycemia: Link to Impaired Glucose Transport in Pancreatic β Cells
Unger, R. H. (1991) · Science · doi:10.1126/science.2006409 · Cited by 263 · see citing works
Arrest of spermatogenesis and defective breast development in mice lacking A-myb
Toscani, A., Mettus, R. V., Coupland, R. W., Simpkins, H., Litvin, J., Orth, J. M., Hatton, K. S., & Reddy, E. P. (1997) · Nature · doi:10.1038/386713a0 · Cited by 224 · see citing works
Self-citationRelaxin-Like Factor Expression as a Marker of Differentiation in the Mouse Testis and Ovary1
Balvers, M., Spiess, A., Domagalski, R., Hunt, N., Kilic, E., Mukhopadhyay, A. K., Hanks, E., Charlton, H. M., & Ivell, R. (1998) · Endocrinology · doi:10.1210/endo.139.6.6046 · Cited by 168 · see citing works
Swenne, I. (1982) · Diabetes · doi:10.2337/diab.31.9.754 · Cited by 154 · see citing works
Interstitial compartment pathology and spermatogenic disruption in testes from impotent diabetic men
Cameron, D. F., Murray, F. T., & Drylie, D. D. (1985) · The Anatomical Record · doi:10.1002/ar.1092130108 · Cited by 146 · see citing works
Functional Maturation and Proliferation of Fetal Pancreatic β-Cells
Hellerström, C., & Swenne, I. (1991) · Diabetes · doi:10.2337/diab.40.2.s89 · Cited by 140 · see citing works
Effects of Aging on the Regenerative Capacity of the Pancreatic B-Cell of the Rat
Swenne, I. (1983) · Diabetes · doi:10.2337/diab.32.1.14 · Cited by 126 · see citing works
Origin, proliferation and differentiation of Leydig cells
Lejeune, H., Habert, R., & Saez, J. (1998) · Journal of Molecular Endocrinology · doi:10.1677/jme.0.0200001 · Cited by 123 · see citing works
The life story of the pancreatic B cell
Hellerstr�m, C. (1984) · Diabetologia · doi:10.1007/bf00262208 · Cited by 115 · see citing works
Insulin; Molecular biology to pathology
(1993) · Comparative Biochemistry and Physiology Part A Physiology · doi:10.1016/0300-9629(93)90488-p · Cited by 101 · see citing works
Gonadal dysfunction in the spontaneously diabetic BB rat
Murray, F. T., Cameron, D. F., & Orth, J. M. (1983) · Metabolism · doi:10.1016/s0026-0495(83)80028-6 · Cited by 63 · see citing works
Höppener, J. W. M., Jansz, H. S., Oosterwijk, C., van Hulst, K. L., Lips, C. J. M., Verbeek, J. S., Capel, P. J., de Koning, E. J. P., & Clark, A. (1994) · Journal of Cellular Biochemistry · doi:10.1002/jcb.240550006 · Cited by 41 · see citing works
Insulin: Molecular Biology to Pathology
(1992) · doi:10.1093/oso/9780199632299.001.0001 · Cited by 41 · see citing works
Della, N. G., Bowtell, D. D. L., & Beck, F. (1995) · Cell and Tissue Research · doi:10.1007/bf00318499 · Cited by 16 · see citing works
Prediction and detection of the fertile period: the markers.
Martinez, A. R., Zinaman, M. J., Vh, J., & Lamprecht, V. M. (1995) · PubMed · Cited by 12 · see citing works
Dunlop, M., Muggli, E., & Clark, S. (1996) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1996.0023 · Cited by 11 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Cell cycle, CDKs and cancer: a changing paradigm
Malumbres, M., & Barbacid, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2602 · Cited by 3,957 · see citing works
Self-citationA genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants
Scott, L. J., Mohlke, K. L., Bonnycastle, L. L., Willer, C. J., Li, Y., Duren, W. L., Erdos, M. R., Stringham, H. M., Chines, P. S., Jackson, A. U., et al. (2007) · Science · doi:10.1126/science.1142382 · Cited by 2,753 · see citing works
Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes
Zeggini, E., Weedon, M. N., Lindgren, C. M., Frayling, T. M., Elliott, K. S., Lango, H., Timpson, N. J., Perry, J. R. B., Rayner, N. W., Freathy, R. M., et al. (2007) · Science · doi:10.1126/science.1142364 · Cited by 2,194 · see citing works
the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Morris, A. P., Voight, B. F., Teslovich, T. M., Ferreira, T., Segrè, A. V., Steinthorsdottir, V., Strawbridge, R. J., Khan, H., Grallert, H., et al. (2012) · Nature Genetics · doi:10.1038/ng.2383 · Cited by 1,912 · see citing works
Gastroenteropancreatic neuroendocrine tumours
Modlin, I. M., Öberg, K., Chung, D. C., Jensen, R. T., de Herder, W. W., Thakker, R. V., Caplin, M. E., Fave, G. D., Kaltsas, G., Krenning, E. P., et al. (2008) · The Lancet Oncology · doi:10.1016/s1470-2045(07)70410-2 · Cited by 1,746 · see citing works
Cdks, cyclins and CKIs: roles beyond cell cycle regulation
Lim, S., & Kaldis, P. (2013) · Development · doi:10.1242/dev.091744 · Cited by 1,483 · see citing works
To cycle or not to cycle: a critical decision in cancer
Malumbres, M., & Barbacid, M. (2001) · Nature reviews. Cancer · doi:10.1038/35106065 · Cited by 1,475 · see citing works
Self-citationMammalian cyclin-dependent kinases
Malumbres, M., & Barbacid, M. (2005) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2005.09.005 · Cited by 1,294 · see citing works
Self-citationTreating cancer with selective CDK4/6 inhibitors
O'Leary, B., Finn, R. S., & Turner, N. C. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.26 · Cited by 1,137 · see citing works
Pancreatic cancer biology and genetics
Bardeesy, N. M., & DePinho, R. A. (2002) · Nature reviews. Cancer · doi:10.1038/nrc949 · Cited by 1,144 · see citing works
Oxidative stress and metabolic disorders: Pathogenesis and therapeutic strategies
Rani, V., Deep, G., Singh, R. K., Palle, K., & Yadav, U. C. S. (2016) · Life Sciences · doi:10.1016/j.lfs.2016.02.002 · Cited by 1,151 · see citing works
“contribute to the development and progression of diabetes [90] (Fig.”
BackgroundCdk1 is sufficient to drive the mammalian cell cycle
Santamarı́a, D., Barrière, C., Cerqueira, A., Hunt, S. L., Tardy, C., Newton, K., Cáceres, J. F., Dubus, P. R., Malumbres, M., & Barbacid, M. (2007) · Nature · doi:10.1038/nature06046 · Cited by 1,096 · see citing works
Self-citationLiving with or without cyclins and cyclin-dependent kinases
Sherr, C. J., & Roberts, J. M. (2004) · Genes & Development · doi:10.1101/gad.1256504 · Cited by 1,089 · see citing works
“Rane et al. 1999; Tsutsui et al. 1999; Zou et al. 2002; Moons et al. 2002 CDK6 Viable Thymic and splenic hypoplasia, and mild defects in hematopoiesis.”
Backgroundp16INK4a 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 · see citing works
Targeting CDK4 and CDK6: From Discovery to Therapy
Sherr, C. J., Beach, D., & Shapiro, G. I. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0894 · Cited by 936 · see citing works
Cell cycle kinases as therapeutic targets for cancer
Lapenna, S., & Giordano, A. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2907 · Cited by 906 · see citing works
Ferron, M., Hinoi, E., Karsenty, G., & Ducy, P. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711119105 · Cited by 900 · see citing works
How stem cells age and why this makes us grow old
Sharpless, N. E., & DePinho, R. A. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2241 · Cited by 843 · see citing works
The Mammalian Ovary from Genesis to Revelation
Edson, M. A., Nagaraja, A. K., & Matzuk, M. M. (2009) · Endocrine Reviews · doi:10.1210/er.2009-0012 · Cited by 828 · see citing works
“Cdk4 / female mice (397, 398) are infertile because of insufficient progesterone production by the CL to allow embryo implantation.”
BackgroundMammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6
Malumbres, M., Sotillo, R., Santamarı́a, D., Galán, J., Cerezo, A., Ortega, S., Dubus, P., & Barbacid, M. (2004) · Cell · doi:10.1016/j.cell.2004.08.002 · Cited by 793 · see citing works
“However, a significant zygous for a Cdk4-null allele, Cdk4 /n (Rane et al., 1999). percentage of them were found dead whereas all Cdk4 / ;Cdk6 / embryos were alive.”
BackgroundSelf-citationBretones, G., Delgado, M. D., & León, J. (2015) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2014.03.013 · Cited by 747 · see citing works
“Nevertheless, systematic knockout of Cdk loci in themouse germline has shown that Cdk2 [16,17], Cdk4 [18,19] and Cdk6 [20] are not essential for cell cycle progression of most cell types, although loss of each of these Cdks results in particular developmental defects.”
BackgroundCyclin D-dependent kinases, INK4 inhibitors and cancer
Ortega, S., Malumbres, M., & Barbacid, M. (2002) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(02)00037-9 · Cited by 774 · see citing works
Self-citationMammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms
Satyanarayana, A., & Kaldis, P. (2009) · Oncogene · doi:10.1038/onc.2009.170 · Cited by 772 · see citing works
“Cdk4 / females are sterile due to a decrease in prolactin producing pituitary lactotrophs (Rane et al., 1999; Tsutsui et al., 1999).”
BackgroundBerthet, C., Aleem, E. A., Coppola, V., Tessarollo, L., & Kaldis, P. (2003) · Current Biology · doi:10.1016/j.cub.2003.09.024 · Cited by 665 · see citing works
The mighty mouse: genetically engineered mouse models in cancer drug development
Sharpless, N. E., & DePinho, R. A. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2110 · Cited by 660 · see citing works
Mouse development and cell proliferation in the absence of D-cyclins
Kozar, K., Ciemerych, M. A., Rebel, V. I., Shigematsu, H., Zagozdzon, A., Sicinska, E., Geng, Y., Yu, Q., Bhattacharya, S., Bronson, R. T., et al. (2004) · Cell · doi:10.1016/j.cell.2004.07.025 · Cited by 647 · see citing works
Cyclin-dependent kinases and cell-cycle transitions: does one fit all?
Hochegger, H., Takeda, S., & Hunt, T. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2510 · Cited by 599 · see citing works
Genetic dissection of mammalian fertility pathways
Matzuk, M. M., & Lamb, D. J. (2002) · Nature Cell Biology · doi:10.1038/ncb-nm-fertilitys41 · Cited by 581 · see citing works
Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases
Hydbring, P., Malumbres, M., & Sicinski, P. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.27 · Cited by 528 · see citing works
Endoplasmic reticulum stress-mediated apoptosis in pancreatic β-cells
Oyadomari, S., Araki, E., & Mori, M. (2002) · APOPTOSIS · doi:10.1023/a:1016175429877 · Cited by 517 · see citing works
Regulatory phases of early liver development: paradigms of organogenesis
Zaret, K. S. (2002) · Nature Reviews Genetics · doi:10.1038/nrg837 · Cited by 507 · see citing works
β cell replication is the primary mechanism for maintaining postnatal β cell mass
Georgia, S. K., & Bhushan, A. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22098 · Cited by 468 · see citing works
“The CDK4-null mice also display a defect in β cell proliferation, indicating that CDK4 acts as the requisite partner for cyclin D2 in controlling cell cycle progression in β cells (21).”
BackgroundA mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors
Crabtree, J. S., Scacheri, P. C., Ward, J. M., Garrett-Beal, L. J., Emmert‐Buck, M. R., Edgemon, K., Lorang, D., Libutti, S. K., Chandrasekharappa, S. C., Marx, S. J., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.3.1118 · Cited by 471 · see citing works
Identification of CDK4 as a target of c-MYC
Hermeking, H., Rago, C., Schuhmacher, M., Li, Q., Barrett, J. F., Obaya, Á. J., O’Connell, B. C., Mateyak, M. K., Tam, W., Kohlhuber, F., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.050586197 · Cited by 471 · see citing works
Very Slow Turnover of β-Cells in Aged Adult Mice
Teta, M., Long, S. Y., Wartschow, L. M., Rankin, M. M., & Kushner, J. A. (2005) · Diabetes · doi:10.2337/diabetes.54.9.2557 · Cited by 465 · see citing works
RETRACTED: Betatrophin: A Hormone that Controls Pancreatic β Cell Proliferation
Yi, P., Park, J.-S., & Melton, D. A. (2013) · Cell · doi:10.1016/j.cell.2013.04.008 · Cited by 449 · see citing works
“The cell-cycle regulators cyclin D1/ D2 and CDK4 promote b cell proliferation (Georgia and Bhushan, 2004; Kushner et al., 2005; Rane et al., 1999), and cell-cyclerelated transcription factors such as E2F1/2 are essential for pancreatic b cell proliferation (Fajas et al.”
BackgroundRetractedRequirement for CDK4 kinase function in breast cancer
Yu, Q., Sicinska, E., Geng, Y., Ahnström, M., Zagozdzon, A., Kong, Y., Gardner, H., Kiyokawa, H., Harris, L. N., Stål, O., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2005.12.012 · Cited by 429 · see citing works
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 · see citing works
Linking cyclins to transcriptional control
Coqueret, O. (2002) · Gene · doi:10.1016/s0378-1119(02)01055-7 · Cited by 428 · see citing works
Cell-cycle inhibitors: three families united by a common cause
Vidal, A., & Koff, A. (2000) · Gene · doi:10.1016/s0378-1119(00)00092-5 · Cited by 429 · see citing works
Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells
Hori, Y., Rulifson, I. C., Tsai, B. C., Heit, J. J., Cahoy, J. D., & Kim, S. K. (2002) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.252618999 · Cited by 463 · see citing works
Keller, M. P., Choi, Y., Wang, P., Belt Davis, D., Rabaglia, M. E., Oler, A. T., Stapleton, D. S., Argmann, C., Schueler, K. L., Edwards, S., et al. (2008) · Genome Research · doi:10.1101/gr.074914.107 · Cited by 377 · see citing works
“reported for the Cdk4 knockout (Rane et al. 1999; Tsutsui et al. 1999) and constitutively active transgenic (Rane et al.”
BackgroundPuyol, M., Martín, A., Dubus, P., Mulero, F., Pizcueta, P., Khan, G., Guerra, C., Santamaría, D., & Barbacid, M. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.05.025 · Cited by 415 · see citing works
“Cdk4 null mice develop diabetes and die at approximately 8 months of age (Rane et al., 1999; Tsutsui et al., 1999).”
BackgroundInfluentialSelf-citationRegulation of pancreatic beta-cell mass
Bouwens, L., & Rooman, I. (2005) · Physiological Reviews · doi:10.1152/physrev.00025.2004 · Cited by 411 · see citing works
“This results in increased beta-cell proliferation in vitro and in transgenic mice, apparently without loss of betacell function (34, 90, 114).”
BackgroundOpposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency
Baker, D. J., Perez-Terzic, C., Jin, F., Pitel, K. S., Niederländer, N. J., Jeganathan, K., Yamada, S., Reyes, S., Rowe, L., Hiddinga, H. J., et al. (2008) · Nature Cell Biology · doi:10.1038/ncb1744 · Cited by 408 · see citing works
Karnik, S. K., Hughes, C. M., Gu, X., Rozenblatt–Rosen, O., McLean, G. W., Xiong, Y., Meyerson, M. M., & Kim, S. K. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503484102 · Cited by 402 · see citing works
Inhibitors of cyclin-dependent kinases as cancer therapeutics.
Whittaker, S. R., Mallinger, A., Workman, P., & Clarke, P. A. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.008 · Cited by 384 · see citing works
“However, cells from other tissues in these embryos proliferate normally, indicating that Cdk4/6 are primarily required for haematopoesis in early development.”
InfluentialBernal‐Mizrachi, E., Wu, W., Stahlhut, S., Welling, C. M., & Permutt, M. A. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13785 · Cited by 382 · see citing works
Redox Control of the Cell Cycle in Health and Disease
Sarsour, E. H., Kumar, M. G., Chaudhuri, L., Kalen, A. L., & Goswami, P. C. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2513 · Cited by 379 · see citing works
“CDK4-knockout mice showed poor b-cell proliferation and insulin-deficient diabetes (249).”
Chen, H., Gu, X., Su, I.-H., Bottino, R., Contreras, J. L., Tarakhovsky, A., & Kim, S. K. (2009) · Genes & Development · doi:10.1101/gad.1742509 · Cited by 366 · see citing works
“Ink4a inhibits specific cyclin-dependent kinases (CDK), including CDK4, a key regulator of b-cell proliferation (Rane et al. 1999), while Arf inhibits the ubiquitin ligase activity of MDM2, thereby stabilizing p53 (for review, see Matheu et al. 2008).”
Backgroundp16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion
Helman, A., Klochendler, A., Azazmeh, N., Gabai, Y., Horwitz, E., Anzi, S., Swisa, A., Condiotti, R., Granit, R. Z., Nevo, Y., et al. (2016) · Nature Medicine · doi:10.1038/nm.4054 · Cited by 351 · see citing works
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 · see citing works
“For instance, when cell cycle arrest is induced specifically in β-cells by overexpression of p27 [24] or by deletion of Cdk4 postnatally, β-cell mass decreases or fails to expand, which would not be the case if neogenesis or transdifferentiation were major sources of new β-cells [25,26].”
BackgroundDiril, M. K., Ratnacaram, C. K., Padmakumar, V. C., Du, T., Wasser, M., Coppola, V., Tessarollo, L., & Kaldis, P. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1115201109 · Cited by 385 · see citing works
Cell-Cycle Therapeutics Come of Age
Ingham, M. A., & Schwartz, G. K. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2016.69.0032 · Cited by 357 · see citing works
Wnt signaling regulates pancreatic β cell proliferation
Rulifson, I. C., Karnik, S. K., Heiser, P. W., ten Berge, D., Chen, H., Gu, X., Taketo, M. M., Nusse, R., Hebrok, M., & Kim, S. K. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701509104 · Cited by 343 · see citing works
Cyclins D2 and D1 Are Essential for Postnatal Pancreatic β-Cell Growth
Kushner, J. A., Ciemerych, M. A., Sicinska, E., Wartschow, L. M., Teta, M., Long, S. Y., Sicinski, P., & White, M. F. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.9.3752-3762.2005 · Cited by 334 · see citing works
“By contrast, constitutively active cdk4 introduced into the mouse genome—by substitution of Arg-24 to Cys-24 that renders cdk4 insensitive to inhibition by p16—expanded the mass of physiologically functional cells (19, 21).”
BackgroundResultBernal‐Mizrachi, E., Wu, W., Stahlhut, S., Welling, C. M., & Permutt, M. A. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200113785 · Cited by 332 · see citing works
“Interestingly, loss of Cdk-4 in mice resulted in insulin-dependent diabetes, while activation of Cdk-4 produced β-cell hyperplasia (31).”
BackgroundCyclin-dependent protein kinases and cell cycle regulation in biology and disease
Pellarin, I., Dall'Acqua, A., Favero, A., Segatto, I., Rossi, V., Crestan, N., Karimbayli, J., Belletti, B., & Baldassarre, G. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02080-z · Cited by 323 · see citing works
The Emerging Genetic Architecture of Type 2 Diabetes
Doria, A., Patti, M., & Kahn, C. R. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.08.006 · Cited by 303 · see citing works
“Interestingly, mice with targeted disruption of this gene have small islets and develop insulin-deficient diabetes, while mice expressing a CDK4 form insensitive to physiological inhibitors exhibit b cell hyperplasia (Rane et al., 1999).”
BackgroundSlawson, C. M., Zachara, N. E., Vosseller, K., Cheung, W. D., Lane, M. D., & Hart, G. W. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m503396200 · Cited by 291 · see citing works
Pancreas and beta-cell development: from the actual to the possible
Murtaugh, L. (2006) · Development · doi:10.1242/dev.02770 · Cited by 303 · see citing works
“With respect to -cell numbers, mice that lack the cyclindependent kinase Cdk4 have a normal complement of -cells at birth, but the failure of these cells to subsequently proliferate produces progressive hyperglycemia (Rane et al., 1999).”
BackgroundThe Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies
Knudsen, E. S., & Witkiewicz, A. K. (2017) · Trends in cancer · doi:10.1016/j.trecan.2016.11.006 · Cited by 285 · see citing works
The CDK4/6 inhibitor revolution — a game-changing era for breast cancer treatment
Morrison, L., Loibl, S., & Turner, N. C. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00840-4 · Cited by 284 · see citing works
“Individual Cdk4 or Cdk6 mouse knockouts are non-lethal 32–34 , reflecting a large degree of functional compensation between CDK4 and CDK6.”
New insights into cyclins, CDKs, and cell cycle control
Sánchez, I., & Dynlacht, B. D. (2005) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2005.02.007 · Cited by 272 · see citing works
E2F transcription factor-1 regulates oxidative metabolism
Blanchet, É., Annicotte, J., Lagarrigue, S., Aguilar, V. M., Clapé, C., Carine Chavey, A., Fritz, V., Casas, F., Apparailly, F., Auwerx, J. H., et al. (2011) · Nature Cell Biology · doi:10.1038/ncb2309 · Cited by 272 · see citing works
Hinoi, E., Gao, N., Jung, D. Y., Yadav, V. K., Yoshizawa, T., Myers, M. G., Chua, S. C., Kim, J. K., Kaestner, K. H., & Karsenty, G. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200809113 · Cited by 267 · see citing works
“In addition, expression of Cdk4 , a gene favoring -cell proliferation in vivo ( Rane et al., 1999 ), was up-regulated 50% in ob/ob islets, and Ki67 immunostaining showed a significant increase in -cell proliferation in ob/ob compared with WT mice ( Fig.”
ResultThe Drosophila Cyclin D–Cdk4 complex promotes cellular growth
Datar, S. A., Jacobs, H. W., de la Cruz, A. F. A., Lehner, C. F., & Edgar, B. A. (2000) · The EMBO Journal · doi:10.1093/emboj/19.17.4543 · Cited by 266 · see citing works
Structural insights into the functional diversity of the CDK–cyclin family
Wood, D. J., & Endicott, J. (2018) · Open Biology · doi:10.1098/rsob.180112 · Cited by 264 · see citing works
Molecular regulation of pancreatic β-cell mass development, maintenance, and expansion
Ackermann, A. M., & Gannon, M. (2007) · Journal of Molecular Endocrinology · doi:10.1677/jme-06-0053 · Cited by 262 · see citing works
“Additionally, mice that express a mutant Cdk4, which cannot be bound and inhibited by p16INK4a (Cdk4R24C/R24C), exhibit postnatal increases in b-cell proliferation and b-cell mass that improve glucose regulation (Rane et al. 1999).”
BackgroundInfluentialGrarup, N., Rose, C. S., Galijatovic, E. A. A., Andersen, G., Nielsen, A. L., Albrechtsen, A., Clausen, J. O., Rasmussen, S. S., Jørgensen, T., Sandbæk, A., et al. (2007) · Diabetes · doi:10.2337/db07-0856 · Cited by 261 · see citing works
Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy
Roberts, P. J., Bisi, J. E., Strum, J. C., Combest, A. J., Darr, D. B., Usary, J. E., Zamboni, W. C., Wong, K.-K., Perou, C. M., & Sharpless, N. E. (2012) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djs002 · Cited by 255 · see citing works
Alonso, L. C., Yokoe, T., Zhang, P., Scott, D. K., Kim, S. K., O'Donnell, C. P., & Garcı́a-Ocaña, A. (2007) · Diabetes · doi:10.2337/db06-1513 · Cited by 252 · see citing works
Of Mice and MEN1: Insulinomas in a Conditional Mouse Knockout
Crabtree, J. S., Scacheri, P. C., Ward, J. M., McNally, S. R., Swain, G. P., Montagna, C., Hager, J. H., Hanahan, D., Edlund, H., Magnuson, M. A., et al. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.17.6075-6085.2003 · Cited by 248 · see citing works
“cdk4 knockout animals (30), on the other hand, are significantly smaller than wild-type littermates and develop insulin- deficient diabetes at an early age.”
BackgroundInfluentialCho, Y. M., Kim, T. H., Lim, S., Choi, S. H., Shin, H. D., Lee, H. K., Park, K. S., & Jang, H. C. (2009) · Diabetologia · doi:10.1007/s00125-008-1196-4 · Cited by 243 · see citing works
CDK inhibitors in cancer therapy: what is next?
Malumbres, M., Pevarello, P., Barbacid, M., & Bischoff, J. R. (2007) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2007.10.012 · Cited by 240 · see citing works
Self-citationThe replication of β cells in normal physiology, in disease and for therapy
Butler, P. C., Meier, J. J., Butler, A. E., & Bhushan, A. (2007) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0647 · Cited by 268 · see citing works
Osteocalcin Promotes β-Cell Proliferation During Development and Adulthood Through Gprc6a
Wei, J., Hanna, T., Suda, N., Karsenty, G., & Ducy, P. F. (2013) · Diabetes · doi:10.2337/db13-0887 · Cited by 237 · see citing works
Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression
Lee, Y., Dominy, J. E., Choi, Y. J., Jurczak, M., Tolliday, N., Camporez, J. P., Chim, H., Lim, J.-H., Ruan, H.-B., Yang, X., et al. (2014) · Nature · doi:10.1038/nature13267 · Cited by 234 · see citing works
Killing cells by targeting mitosis
Manchado, E., Guillamot, M., & Malumbres, M. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2011.197 · Cited by 231 · see citing works
Priorities for Improving the Management of Gastroenteropancreatic Neuroendocrine Tumors
Modlin, I. M., Moss, S. F., Chung, D. C., Jensen, R. T., & Snyderwine, E. G. (2008) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djn275 · Cited by 225 · see citing works
Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice
FOTI, D. P., CHIEFARI, E. D., Fedele, M., Iuliano, R., Brunetti, L., Paonessa, F., Manfioletti, G., Barbetti, F., Brunetti, A., Croce, C. M., et al. (2005) · Nature Medicine · doi:10.1038/nm1254 · Cited by 221 · see citing works
Yoshizawa, T., Hinoi, E., Jung, D. Y., Kajimura, D., Ferron, M., Seo, J. H., Graff, J. M., Kim, J. K., & Karsenty, G. (2009) · Journal of Clinical Investigation · doi:10.1172/jci39366 · Cited by 221 · see citing works
Cyclin D-CDK4/6 functions in cancer
Gao, X., Leone, G. W., & Wang, H. (2020) · Advances in cancer research · doi:10.1016/bs.acr.2020.02.002 · Cited by 220 · see citing works
Uchida, T., Nakamura, T., Hashimoto, N., Matsuda, T., Kotani, K., Sakaue, H., Kido, Y., Hayashi, Y., Nakayama, K. I., White, M. F., et al. (2005) · Nature Medicine · doi:10.1038/nm1187 · Cited by 218 · see citing works
Physiological Relevance of Cell Cycle Kinases
Malumbres, M. (2011) · Physiological Reviews · doi:10.1152/physrev.00025.2010 · Cited by 215 · see citing works
“In quiescent hair follicle stem cells, Cdk4 is repressed by the nuclear factor of activated T cells c1 (NFATc1).”
BackgroundInfluentialWang, H.-Y., Maechler, P., Antinozzi, P., Hagenfeldt, K., & Wollheim, C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m006612200 · Cited by 200 · see citing works
Wide spectrum of tumors in knock‐in mice carrying a Cdk4 protein insensitive to INK4 inhibitors
Sotillo, R., Dubus, P., Martn, J., de la Cueva, E., Ortega, S., Malumbres, M., & Barbacid, M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.23.6637 · Cited by 208 · see citing works
Self-citationFátrai, S., Elghazi, L., Balcázar, N., CRAS-MÉNEUR, C. M. H., Krits, I., Kiyokawa, H., & Bernal‐Mizrachi, E. (2006) · Diabetes · doi:10.2337/diabetes.55.02.06.db05-0757 · Cited by 206 · see citing works
Diabetes mellitus—advances and challenges in human β-cell proliferation
Wang, P., Fiaschi‐Taesch, N., Vasavada, R. C., Scott, D. K., Garcı́a-Ocaña, A., & Stewart, A. F. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.9 · Cited by 204 · see citing works
Tigan, A.-S., Bellutti, F., Kollmann, K., Tebb, G., & Sexl, V (2016) · Oncogene · doi:10.1038/onc.2015.407 · Cited by 204 · see citing works
Molecular Control of Cell Cycle Progression in the Pancreatic β-Cell
Cózar‐Castellano, I., Fiaschi‐Taesch, N., Bigatel, T. A., Takane, K. K., Garcı́a-Ocaña, A., Vasavada, R. C., & Stewart, A. F. (2006) · Endocrine Reviews · doi:10.1210/er.2006-0004 · Cited by 197 · see citing works
CDK4: A Key Player in the Cell Cycle, Development, and Cancer
Baker, S. J., & Reddy, E. P. (2012) · Genes & Cancer · doi:10.1177/1947601913478972 · Cited by 197 · see citing works
Self-citationLin, H., Lee, J.-H., Yadav, H., Kamaraju, A. K., Liu, E. V., Zhigang, D., Vieira, A., Kim, S., Collins, H. W., Matschinsky, F. M., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m805379200 · Cited by 189 · see citing works
Self-citationNebenfuehr, S., Kollmann, K., & Sexl, V. (2020) · International Journal of Cancer · doi:10.1002/ijc.33054 · Cited by 185 · see citing works
“Moreover, CDK4-null mice are smaller in size and infertile.(25,26)”
BackgroundDrosophila Cdk4 is required for normal growth and is dispensable for cell cycle progression
Meyer, C. A., Jacobs, H. W., Datar, S. A., Du, W., Edgar, B. A., & Lehner, C. F. (2000) · The EMBO Journal · doi:10.1093/emboj/19.17.4533 · Cited by 187 · see citing works
Therapeutic Targeting of the Cyclin D3:CDK4/6 Complex in T Cell Leukemia
Sawai, C. M., Freund, J., Oh, P., Ndiaye-Lobry, D., Bretz, J. C., Strikoudis, A., Genesca, L., Trimarchi, T., Kelliher, M. A., Clark, M., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.09.016 · Cited by 183 · see citing works
“…and progression of T cell leukemia and, at the same time, cause minimal hematologic side effects, based on the phenotypes of animals lacking expression of cyclin D3 or CDK4/6 (Cooper et al., 2006; Malumbres et al., 2004; Rane et al., 1999; Sicinska et al., 2003, 2006; Tsutsui et al., 1999).”
Type 2 Diabetes and the Aging Pancreatic Beta Cell
Gunasekaran, U., & GANNON, M. A. (2011) · Aging · doi:10.18632/aging.100350 · Cited by 183 · see citing works
Cyclin D1 Determines Mitochondrial Function InVivo
Sakamaki, T., Casimiro, M. C., Ju, X., Quong, A. A., Katiyar, S., Liu, M., Jiao, X., Li, A., Zhang, X., Lu, Y., et al. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.02074-05 · Cited by 184 · see citing works
“The cdk4 / 3T3 fibroblasts were previously described (48).”
BackgroundA GRFa2/Prop1/Stem (GPS) Cell Niche in the Pituitary
García-Lavandeira, M., Quereda, V., Flores, I., Sáez, C., Díaz-Rodríguez, E., Japón, M. Á., Ryan, A. K., Blasco, M. A., Diéguez, C., Malumbres, M., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004815 · Cited by 182 · see citing works
“Cdk4-deficient mice in which Cdk4 has been inactivated by the insertion of a neomycin-resistant (neo) cassette [Cdk4(n/n) mice] [48] display hypoplastic pituitaries with a dramatic decrease of all hormonesecretory cells in the AP during postnatal life (Figure 6A–B, center and Figure S4).”
Backgroundβ-cell failure as a complication of diabetes
Chang-Chen, K. J., Mullur, R., & Bernal-Mizrachi, E. (2008) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-008-9101-5 · Cited by 225 · see citing works
“binding by INK4 proteins exhibit islet hyperplasia [15, 18].”
- Authors
- Rane, S. G., Dubus, P., Mettus, R. V., Galbreath, E. J., Boden, G., Reddy, E. P., & Barbacid, M.
- Affiliations
- Temple University (US)
- Université Bordeaux Segalen (FR)
- Eli Lilly (United States) (US)
- Spanish National Cancer Research Centre (ES)
- Corresponding author
- Reddy, E. Premkumar
- Barbacid, Mariano
- Venue
- Nature Genetics
- Published
- 1999-05
- Volume
- 22
- Issue
- 1
- Pages
- 44-52
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- DOI
- 10.1038/8751
- OpenAlex
- W1520222296
- Cited by
- 700
- References
- 44
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 12 · 2023: 15 · 2022: 16 · 2021: 11 · 2020: 23 · 2019: 17 · 2018: 19 · 2017: 28 · 2016: 20 · 2015: 29 · 2014: 33 · 2013: 33 · 2012: 32
- FWCI
- 17.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag007988-10, 5r01aa010221-03)
- National Institute on Alcohol Abuse and Alcoholism (R01-AA-10221)
- National Institute on Aging (R01-AG07988)
- National Center for Research Resources (M01RR000349, RR-00349)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- CDK4, insulin-deficient diabetes, beta-cell hyperplasia, pancreatic islets, p16INK4a, cell cycle regulation, S phase delay, embryonic fibroblasts, infertility, cell proliferation
- MeSH terms
- Animals, Cell Line, Diabetes Mellitus, Enzyme Activation, Female, Gene Expression Regulation, Hyperplasia, Infertility, Female, Infertility, Male, Insulin, Islets of Langerhans, Male, Mice, Inbred Strains, Proto-Oncogene Proteins, Spermatogenesis, Mutagenesis, Site-Directed, Cyclin-Dependent Kinases, Cyclin-Dependent Kinase 4, Mice
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