Cited by 395Cancer-related Molecular PathwaysProtein Kinase Regulation and GTPase SignalingMicrotubule and mitosis dynamics

Targeted Disruption of CDK4 Delays Cell Cycle Entry with Enhanced p27 Kip1 Activity

Open access
Tsutsui, Tateki, Hesabi, Bahar, Moons, David S., Pandolfi, Pier Paolo, Hansel, Kimberly S., Koff, Andrew, Kiyokawa, Hiroaki·1999·Molecular and Cellular Biology

Abstract

The mechanism by which cyclin-dependent kinase 4 (CDK4) regulates cell cycle progression is not entirely clear. Cyclin D/CDK4 appears to initiate phosphorylation of retinoblastoma protein (Rb) leading to inactivation of the S-phase-inhibitory action of Rb. However, cyclin D/CDK4 has been postulated to act in a noncatalytic manner to regulate the cyclin E/CDK2-inhibitory activity of p27(Kip1) by sequestration. In this study we investigated the roles of CDK4 in cell cycle regulation by targeted disruption of the mouse CDK4 gene. CDK4(-/-) mice survived embryogenesis and showed growth retardation and reproductive dysfunction associated with hypoplastic seminiferous tubules in the testis and perturbed corpus luteum formation in the ovary. These phenotypes appear to be opposite to those of p27-deficient mice such as gigantism and gonadal hyperplasia. A majority of CDK4(-/-) mice developed diabetes mellitus by 6 weeks, associated with degeneration of pancreatic islets. Fibroblasts from CDK4(-/-) mouse embryos proliferated similarly to wild-type embryonic fibroblasts under conditions that promote continuous growth. However, quiescent CDK4(-/-) fibroblasts exhibited a substantial ( approximately 6-h) delay in S-phase entry after serum stimulation. This cell cycle perturbation by CDK4 disruption was associated with increased binding of p27 to cyclin E/CDK2 and diminished activation of CDK2 accompanied by impaired Rb phosphorylation. Importantly, fibroblasts from CDK4(-/-) p27(-/-) embryos displayed partially restored kinetics of the G(0)-S transition, indicating the significance of the sequestration of p27 by CDK4. These results suggest that at least part of CDK4's participation in the rate-limiting mechanism for the G(0)-S transition consists of controlling p27 activity.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1128/mcb.19.10.7011

Cites

64 of 64 references verified0 citation errors · 0 not checkable

Statistics

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.

A few free checks a day · papers already verified open instantly · results are public

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?

  • 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 [86]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Tsutsui, T., Hesabi, B., Moons, D. S., Pandolfi, P. P., Hansel, K. S., Koff, A., & Kiyokawa, H.
Affiliations
  • University of Illinois Urbana-Champaign (US)
  • Department of Human Genetics
  • Memorial Sloan Kettering Cancer Center (US)
Venue
Molecular and Cellular Biology
Published
1999-10
Volume
19
Issue
10
Pages
7011-7019
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
OpenAlex
W1932315029
Cited by
395
References
64
Citations by year
2026: 5 · 2025: 7 · 2024: 5 · 2023: 10 · 2022: 4 · 2021: 7 · 2020: 8 · 2019: 9 · 2018: 8 · 2017: 7 · 2016: 10 · 2015: 12 · 2014: 16 · 2013: 11 · 2012: 18
FWCI
6.20
Type
journal article
Language
en
Open access
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Cancer Society
  • National Institutes of Health
  • University of Illinois at Urbana-Champaign
  • National Institute of General Medical Sciences (GM 52597, R01GM052597)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
Keywords
CDK4, p27, cell cycle regulation, retinoblastoma protein phosphorylation, cyclin E/CDK2, diabetes mellitus, corpus luteum formation, fibroblast proliferation, S phase entry
MeSH terms
Animals, Atrophy, Cell Cycle, Corpus Luteum, Diabetes Mellitus, Female, Glycosuria, Homozygote, Male, Mice, Mutant Strains, Microtubule-Associated Proteins, Protein Binding, Proto-Oncogene Proteins, Seminiferous Tubules, Tissue Distribution, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Cyclin-Dependent Kinases, Tumor Suppressor Proteins, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice

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