Abolition of Cyclin-Dependent Kinase Inhibitor p16 Ink4a and p21 Cip1/Waf1 Functions Permits Ras-Induced Anchorage-Independent Growth in Telomerase-Immortalized Human Fibroblasts
Open accessAbstract
Human cells are more resistant to both immortalization and malignant transformation than rodent cells. Recent studies have established the basic genetic requirements for the transformation of human cells, but much of this work relied on the expression of transforming proteins derived from DNA tumor viruses. We constructed an isogenic panel of human fibroblast cell lines using a combination of gene targeting and ectopic expression of dominantly acting mutants of cellular genes. Abolition of p21(Cip1/Waf1) and p16(Ink4a) functions prevented oncogenically activated Ras from inducing growth arrest and was sufficient for limited anchorage-independent growth but not tumorigenesis. Deletion of the tumor suppressor p53 combined with abolition of p16(Ink4a) function failed to mimic the introduction of simian virus 40 large T antigen, indicating that large T antigen may target additional cellular functions. Ha-Ras and Myc cooperated only to a limited extent, but in the absence of Ras, Myc cooperated strongly with the simian virus 40 small t antigen to elicit aggressive anchorage-independent growth. The experiments reported here further define specific components of human transformation pathways.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
The pathway activated by p53 or Rb converges into a common senescence effector mechanism that has yet to be identified.
“This well-known fact (28, 29, 43, 48) indicates that the pathway activated by p53 or Rb converges into a common senescence effector mechanism that has yet to be identified.”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [48]
These mitochondrial changes appeared before the senescence cell cycle arrest and were totally prevented by disabling the p53 and Rb tumor suppressors.
“These changes appeared before the senescence cell cycle arrest and were totally prevented by disabling the p53 and Rb tumor suppressors, which are known to regulate independently the senescence effector mechanism (28, 29, 43, 48).”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [48]
The shRNA against p53 or E7 did not rescue the senescence phenotype.
“Of note, as reported before (28, 29, 43, 48), the shRNA against neither p53 nor E7 rescued the senescence phenotype (see Fig. S3 in the supplemental material)”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [48]
Ras-induced senescence in human cells can be mediated by either the p53 or the Rb family of tumor suppressors.
“Ras-induced senescence in human cells can be mediated by either the p53 or the Rb family of tumor suppressors (28, 29, 43, 48).”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [48]
Cites
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,178 · cited 9× · see citing works
“In rodent cells, Ras-induced arrest can be eliminated by lesions in either the p53 or Rb pathways (58); however, in human cells, both pathways must be compromised (18, 44, 58 , 75).”
BackgroundMethodResultInfluentialCreation of human tumour cells with defined genetic elements
Hahn, W. C., Counter, C. M., Lundberg, A. S., Beijersbergen, R. L., Brooks, M. W., & Weinberg, R. A. (1999) · Nature · doi:10.1038/22780 · Cited by 2,345 · see citing works
Self-citationThe RB and p53 pathways in cancer
Sherr, C. J., & McCormick, F. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00102-2 · Cited by 1,690 · see citing works
Ruley, H. E. (1983) · Nature · doi:10.1038/304602a0 · Cited by 1,248 · see citing works
Kiyono, T., Foster, S. A., Koop, J. I., McDougall, J. K., Galloway, D. A., & Klingelhutz, A. J. (1998) · Nature · doi:10.1038/23962 · Cited by 1,206 · see citing works
Sherr, C. J., & DePinho, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)00046-5 · Cited by 745 · see citing works
Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions
Ramirez, R. D., Morales, C. P., Herbert, B.-S., Rohde, J. M., Passons, C., Shay, J. W., & Wright, W. E. (2001) · Genes & Development · doi:10.1101/gad.859201 · Cited by 444 · cited 1× · see citing works
“The extent to which mutations in these pathways are necessary for immortalization in addition to the expression of telomerase has been controversial (26, 47 , 50, 61).”
BackgroundOpposing Effects of Ras on p53
Ries, S., Biederer, C., Woods, D., Shifman, O., Shirasawa, S., Sasazuki, T., McMahon, M., Oren, M., & McCormick, F. (2000) · Cell · doi:10.1016/s0092-8674(00)00123-9 · Cited by 357 · see citing works
Rheinwald, J. G., Hahn, W. C., Ramsey, M. R., Wu, J. Y., Guo, Z., Tsao, H., De Luca, M., Catricalà, C., & O'Toole, K. M. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.14.5157-5172.2002 · Cited by 338 · see citing works
Role of p14<sup>ARF</sup> in Replicative and Induced Senescence of Human Fibroblasts
Wei, W., Hemmer, R. M., & Sedivy, J. M. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.20.6748-6757.2001 · Cited by 217 · see citing works
Self-citationWide 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
Brown, D. R., Thomas, C. A., & Palit Deb, S. (1998) · The EMBO Journal · doi:10.1093/emboj/17.9.2513 · Cited by 148 · see citing works
Evans, D. R. H., Myles, T., Hofsteenge, J., & Hemmings, B. A. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.34.24038 · Cited by 65 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Ras oncogenes: split personalities
Karnoub, A. E., & Weinberg, R. A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2438 · Cited by 1,467 · see citing works
Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence
Moiseeva, O., Bourdeau, V., Roux, A., Deschênes-Simard, X., & Ferbeyre, G. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01868-08 · Cited by 408 · see citing works
Multiple pathways regulated by the tumor suppressor PP2A in transformation
Westermarck, J., & Hahn, W. C. (2008) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2008.02.001 · Cited by 344 · see citing works
Self-citationMultiple microRNAs rescue from Ras-induced senescence by inhibiting p21Waf1/Cip1
Borgdorff, V, Lleonart, M. E., Bishop, C. L., Fessart, D., Bergin, A. H., Overhoff, M. G., & Beach, D. H. (2010) · Oncogene · doi:10.1038/onc.2009.497 · Cited by 160 · see citing works
Wei, W., Herbig, U., Wei, S., Dutriaux, A., & Sedivy, J. M. (2003) · The EMBO Reports · doi:10.1038/sj.embor.7400001 · Cited by 88 · see citing works
Self-citationBond, J., Jones, C., Haughton, M., DeMicco, C., Kipling, D., & Wynford-Thomas, D. (2004) · Experimental Cell Research · doi:10.1016/j.yexcr.2003.09.021 · Cited by 49 · see citing works
- Authors
- Wei, W., Jobling, W. A., Chen, W., Hahn, W. C., & Sedivy, J. M.
- Affiliations
- Brown University (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Sedivy, John M.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2003-04
- Volume
- 23
- Issue
- 8
- Pages
- 2859-2870
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC152557
- OpenAlex
- W2081570461
- Cited by
- 68
- References
- 13
- Citations by year
- 2021: 3 · 2019: 1 · 2018: 2 · 2017: 3 · 2015: 1 · 2014: 2 · 2013: 2 · 2012: 2
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG16694, R01AG016694)
- National Cancer Institute (K01CA94223, K01CA094223)
- National Institute of General Medical Sciences (R01GM41690, R01GM041690)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- p16INK4a, p21, cyclin-dependent kinase inhibitors, oncogenic Ras, anchorage-independent growth, p53 deletion, SV40 large T antigen, SV40 small t antigen, c-Myc, Ha-ras, tumor suppressor, isogenic cell lines
- MeSH terms
- Antigens, Polyomavirus Transforming, Cell Adhesion, Cell Division, Cell Line, Transformed, Cell Transformation, Neoplastic, Humans, Cyclins, Genes, myc, Gene Targeting, ras Proteins, Telomerase, Cyclin-Dependent Kinase Inhibitor p16, Genes, p16, Cyclin-Dependent Kinase Inhibitor p21
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
