Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0023473 (
chronic myeloid leukemia
)
18,916
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
CDKN3
(cyclin-dependent kinase inhibitor 3), a dual specificity protein phosphatase, dephosphorylates cyclin-dependent kinases (CDKs) and thus functions as a key negative regulator of cell cycle progression. Deregulation or mutations of CDNK3 have been implicated in various cancers. However, the role of
CDKN3
in Bcr-Abl-mediated
chronic myelogenous leukemia
(
CML
) remains unknown. Here we found that
CDKN3
acts as a tumor suppressor in Bcr-Abl-mediated leukemogenesis. Overexpression of
CDKN3
sensitized the K562 leukemic cells to imanitib-induced apoptosis and dramatically inhibited K562 xenografted tumor growth in nude mouse model. Ectopic expression of
CDKN3
significantly reduced the efficiency of Bcr-Abl-mediated transformation of FDCP1 cells to growth factor independence. In contrast, depletion of
CDKN3
expression conferred resistance to imatinib-induced apoptosis in the leukemic cells and accelerated the growth of xenograph leukemia in mice. In addition, we found that
CDKN3
mutant (
CDKN3
-C140S) devoid of the phosphatase activity failed to affect the K562 leukemic cell survival and xenografted tumor growth, suggesting that the phosphatase of
CDKN3
was required for its tumor suppressor function. Furthermore, we observed that overexpression of
CDKN3
reduced the leukemic cell survival by dephosphorylating CDK2, thereby inhibiting CDK2-dependent XIAP expression. Moreover, overexpression of
CDKN3
delayed G1/S transition in K562 leukemic cells. Our results highlight the importance of
CDKN3
in Bcr-Abl-mediated leukemogenesis, and provide new insights into diagnostics and therapeutics of the leukemia.
...
PMID:A critical role of CDKN3 in Bcr-Abl-mediated tumorigenesis. 2536 Jun 22
