Roles of PI3K /Akt activated MDM2 and p21 in mammary development and tumorigenesis
Breast cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death among women in the United States. Activation of the PI3K/Akt pathway has been implicated in the development of a variety of human malignancies, including a significant percentage of human breast cancers, through protecting cells from undergoing apoptosis. A number of Akt downstream targets have been indentified which are associated with apoptotic functions, such as MDM2 and p21. Amplification or overexpression of MDM2 is involved in a variety of human tumors through degrading tumor suppressors, such as p53. Akt is able to inhibit the function of p53 through phosphorylation of its downstream target MDM2 on serine166 and serine 186. ^ Although p21 is a universal inhibitor of cyclin-CDKs, it has been revealed to be a multifaceted protein that it also has an “oncoprotein”-like property, which was demonstrated in different types of human cancers, including human breast cancers One of the mechanisms that p21 exerts its oncogenic function is through protecting cells from apoptosis, which is closely related to its cytoplasmic localization. Studies have shown that Akt can phosphorylate p21 at threonine 145 (T145), resulting in the cytoplasmic localization of p21 and an increased resistance to apoptosis. ^ To directly study the physiological roles of Akt-mediated MDM2 and p21 phosphorylation in mammary development and tumorigenesis, the transgenic mice expressing constitutively activated form of MDM2 (MDM2DDS166D/S186D ) and p21 (p21DT145D), which mimic the active phosphorylated state of the two proteins by Akt, specifically in the mammary epithelium was generated respectively. We found that activation of MDM2 delayed the mammary gland involution process by interfering with apoptotic process. Expression of activated MDM2 accelerated the tumor progression in MMTV/neu transgenic mice. The interfered apoptosis in mammary gland involution and accelerated tumor progression corresponded with the decreased expression of p53. In addition, the results here showed that overexpression of Akt activated p21 could accelerate the tumor onset and promote lung metastasis in MMTV/ neu mice. ^ Taken together, these observations suggest that activation of MDM2 by Akt can contribute to tumor progression. In addition, our results provided the evidence that p21, especially the cytoplasmic p21 has an oncogenic role in promoting mammary tumorigenesis and metastasis. These studies will provide important insights into the physiological roles of downstream effectors of PI3K/Akt pathway in mammary tumorigenesis and metastasis. The information gained from the studies maybe useful in the long run for clinical trials on the efficacy of therapeutics directed against the PI3K/Akt pathway. ^
Biology, Molecular|Health Sciences, Oncology
Cheng, Xiaoyun, "Roles of PI3K /Akt activated MDM2 and p21 in mammary development and tumorigenesis" (2009). Texas Medical Center Dissertations (via ProQuest). AAI3394957.