ArticleOncogene2015
MEN1 tumorigenesis in the pituitary and pancreatic islet requires Cdk4 but not Cdk2.
Article in Oncogene, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
23 citing papers in PubMed, 40 citations in OpenAlex.
- Targeting CDKs in cancer therapy: advances in PROTACs and molecular glues.NPJ precision oncology · 2025Review
- Alternative splicing generates isoform diversity inEndocrine oncology (Bristol, England) · 2024Article
- Molecular and Clinical Spectrum of Primary Hyperparathyroidism.Endocrine reviews · 2023Article
- Pituitary Tumorigenesis-Implications for Management.Medicina (Kaunas, Lithuania) · 2023Review
- Combined Targeting of Pathogenetic Mechanisms in Pancreatic Neuroendocrine Tumors Elicits Synergistic Antitumor Effects.Cancers · 2022Article
- Multiple Endocrine Neoplasia Type 1: Latest Insights.Endocrine reviews · 2021Review
- Article
- Genetic background influences tumour development in heterozygous Men1 knockout mice.Endocrine connections · 2020Article
- Is there a CDKN2A-centric networkOncoTargets and therapy · 2020Review
- MENIN loss as a tissue-specific driver of tumorigenesis.Molecular and cellular endocrinology · 2018Review
- Article
- Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets.Endocrine connections · 2018Review
- The future: genetics advances in MEN1 therapeutic approaches and management strategies.Endocrine-related cancer · 2017Review
- siRNA Delivery for Control of Cyclin D1 and E2F1 Expression in Crohn's Disease.Translational medicine @ UniSa · 2017Article
- siRNA Delivery for Control of Cyclin D1 and E2F1 Expression in Crohn's Disease.Translational medicine @ UniSa · 2017Article
- Article
- Somatotroph-SpecificJournal of the Endocrine Society · 2017Article
- Cell cycle proteins as promising targets in cancer therapy.Nature reviews. Cancer · 2017Review
- Article
- Animal models of pituitary neoplasia.Molecular and cellular endocrinology · 2016Review
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
Recent studies suggest that physiological and tumorigenic proliferation of mammalian cells is controlled by multiple cyclin-dependent kinases (CDKs) largely in tissue-specific manners. We and others previously demonstrated that adult mice deficient for the Cyclin D partner CDK4 (Cdk4(-/-) mice) exhibit hypoplasia in the pituitary and pancreatic islet due to primary postnatal defects in proliferation. Intriguingly, those neuroendocrine tissues affected in Cdk4(-/-) mice are the primary targets of tumorigenesis in the syndrome of multiple endocrine neoplasia type-1 (MEN1). Mice with heterozygous disruption of the tumor suppressor Men1 gene (Men1(+/-)) develop tumors in the pituitary, pancreatic islets and other neuroendocrine tissues, which is analogous to humans with MEN1 mutations. To explore the genetic interactions between loss of Men1 and activation of CDKs, we examined the impact of Cdk4 or Cdk2 disruption on tumorigenesis in Men1(+/-) mice. A majority of Men1(+/-) mice with wild-type CDKs developed pituitary and islet tumors by 15 months of age. Strikingly, Men1(+/-); Cdk4(-/-) mice did not develop any tumors, and their islets and pituitaries remained hypoplastic with decreased proliferation. In contrast, Men1(+/-); Cdk2(-/-) mice showed pituitary and islet tumorigenesis comparable to those in Men1(+/-) mice. Pituitaries of Men1(+/-); Cdk4(-/-) mice showed no signs of loss of heterozygosity (LOH) in the Men1 locus, whereas tumors in Men1(+/-) mice and Men1(+/-); Cdk2(-/-) mice exhibited LOH. Consistently, CDK4 knockdown in INS-1 insulinoma cells inhibited glucose-stimulated cell cycle progression with a significant decrease in phosphorylation of retinoblastoma protein (RB) at specific sites including Ser780. CDK2 knockdown had minimum effects on RB phosphorylation and cell cycle progression. These data suggest that CDK4 is a critical downstream target of MEN1-dependent tumor suppression and is required for tumorigenic proliferation in the pituitary and pancreatic islet, whereas CDK2 is dispensable for tumorigenesis in these neuroendocrine cell types.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.