Loss of Cdk2 and cyclin A2 impairs cell proliferation and tumorigenesis
Gopinathan, Lakshmi ; Tan, Shawn Lu Wen ; Padmakumar, V. C. ; Coppola, Vincenzo ; Tessarollo, Lino and Kaldis, Philipp LU
(2014)
In Cancer Research
74(14).
p.3870-3879
- Abstract
Cell-cycle inhibition has yet to offer a generally effective approach to cancer treatment, but a full evaluation of different combinations of cell-cycle inhibitors has not been evaluated. Cyclin A2, a core component of the cell cycle, is often aberrantly expressed in cancer where it may impact cell proliferation. In this study, we investigated the role of cyclin A2 in tumorigenesis using a conditional genetic knockout mouse model. Cyclin A2 deletion in oncogene-transformed mouse embryonic fibroblasts (MEF) suppressed tumor formation in immunocompromised mice. These findings were confirmed in mice with cyclin A2-deficient hepatocytes, where a delay in liver tumor formation was observed. Because cyclin A2 acts in complex with Cdk2 in the... (More)
Cell-cycle inhibition has yet to offer a generally effective approach to cancer treatment, but a full evaluation of different combinations of cell-cycle inhibitors has not been evaluated. Cyclin A2, a core component of the cell cycle, is often aberrantly expressed in cancer where it may impact cell proliferation. In this study, we investigated the role of cyclin A2 in tumorigenesis using a conditional genetic knockout mouse model. Cyclin A2 deletion in oncogene-transformed mouse embryonic fibroblasts (MEF) suppressed tumor formation in immunocompromised mice. These findings were confirmed in mice with cyclin A2-deficient hepatocytes, where a delay in liver tumor formation was observed. Because cyclin A2 acts in complex with Cdk2 in the cell cycle, we explored a hypothesized role for Cdk2 dysregulation in this effect through conditional deletions of both genes. In oncogene-transformed MEFs lacking both genes, tumor formation was strongly suppressed in a manner associated with decreased proliferation, premature senescence, and error-prone recovery from serum deprivation after immortalization. Whereas loss of cyclin A2 led to a compensatory increase in Cdk1 activity, this did not occur with loss of both Cdk2 and cyclin A2. Our work offers a rationale to explore combinations of Cdk1 and Cdk2 inhibitors as a general approach in cancer therapy.
(Less)
- author
- Gopinathan, Lakshmi
; Tan, Shawn Lu Wen
; Padmakumar, V. C.
; Coppola, Vincenzo
; Tessarollo, Lino
and Kaldis, Philipp
LU
- publishing date
- 2014-07
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cancer Research
- volume
- 74
- issue
- 14
- pages
- 10 pages
- publisher
- American Association for Cancer Research Inc.
- external identifiers
-
- scopus:84904254085
- pmid:24802190
- ISSN
- 0008-5472
- DOI
- 10.1158/0008-5472.CAN-13-3440
- language
- English
- LU publication?
- no
- id
- 6a5d45a6-4ef1-465c-8768-66f945685452
- date added to LUP
- 2019-09-18 13:54:19
- date last changed
- 2024-06-13 04:21:26
@article{6a5d45a6-4ef1-465c-8768-66f945685452,
abstract = {{<p>Cell-cycle inhibition has yet to offer a generally effective approach to cancer treatment, but a full evaluation of different combinations of cell-cycle inhibitors has not been evaluated. Cyclin A2, a core component of the cell cycle, is often aberrantly expressed in cancer where it may impact cell proliferation. In this study, we investigated the role of cyclin A2 in tumorigenesis using a conditional genetic knockout mouse model. Cyclin A2 deletion in oncogene-transformed mouse embryonic fibroblasts (MEF) suppressed tumor formation in immunocompromised mice. These findings were confirmed in mice with cyclin A2-deficient hepatocytes, where a delay in liver tumor formation was observed. Because cyclin A2 acts in complex with Cdk2 in the cell cycle, we explored a hypothesized role for Cdk2 dysregulation in this effect through conditional deletions of both genes. In oncogene-transformed MEFs lacking both genes, tumor formation was strongly suppressed in a manner associated with decreased proliferation, premature senescence, and error-prone recovery from serum deprivation after immortalization. Whereas loss of cyclin A2 led to a compensatory increase in Cdk1 activity, this did not occur with loss of both Cdk2 and cyclin A2. Our work offers a rationale to explore combinations of Cdk1 and Cdk2 inhibitors as a general approach in cancer therapy.</p>}},
author = {{Gopinathan, Lakshmi and Tan, Shawn Lu Wen and Padmakumar, V. C. and Coppola, Vincenzo and Tessarollo, Lino and Kaldis, Philipp}},
issn = {{0008-5472}},
language = {{eng}},
number = {{14}},
pages = {{3870--3879}},
publisher = {{American Association for Cancer Research Inc.}},
series = {{Cancer Research}},
title = {{Loss of Cdk2 and cyclin A2 impairs cell proliferation and tumorigenesis}},
url = {{http://dx.doi.org/10.1158/0008-5472.CAN-13-3440}},
doi = {{10.1158/0008-5472.CAN-13-3440}},
volume = {{74}},
year = {{2014}},
}