Activation of p21(CIP1/WAF1) in mammary epithelium accelerates mammary tumorigenesis and promotes lung metastasis.
While p21 is well known to inhibit cyclin-CDK activity in the nucleus and it has also been demonstrated to have oncogenic properties in different types of human cancers. In vitro studies showed that the oncogenic function of p21is closely related to its cytoplasmic localization. However, it is unclear whether cytoplasmic p21 contributes to tumorigenesis in vivo. To address this question, we generated transgenic mice expressing the Akt-phosphorylated form of p21 (p21T145D) in the mammary epithelium. The results showed that Akt-activated p21 was expressed in the cytoplasm of mammary epithelium. Overexpression of Akt-activated p21 accelerated tumor onset and promoted lung metastasis in MMTV/neu mice, providing evidence that p21, especially cytoplasmic phosphorylated p21, has an oncogenic role in promoting mammary tumorigenesis and metastasis.
Department of Molecular and Cellular Oncology, The University of Texas, M D Anderson Cancer Center, Houston, TX 77030, USA.
Xiaoyun
X
Cheng
Weiya
W
Xia
Jer-Yen
JY
Yang
Jennifer L
JL
Hsu
Chao-Kai
CK
Chou
Hui-Lung
HL
Sun
Shannon L
SL
Wyszomierski
Gordon B
GB
Mills
William J
WJ
Muller
Dihua
D
Yu
Mien-Chie
MC
Hung
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051057:Proto-Oncogene Proteins c-akt