Role Of P21-activated Kinase 1 In Regulating Mammary Gland Morphogenesis And Functional Differentiation | 16399
Journal of Clinical & Experimental Pathology
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Pak1 kinase is a critical signaling molecule which regulates cell survival, proliferation and directional locomotion. In the
study of the mammary gland development, we found that Pak1 was highly expressed periodically regulated in the mammary
glands, especially during pregnancy and lactation, but the other two members of the same family, Pak2 and Pak3, were not. We
therefore generated two Pak1 transgenic mice, one with dominant-negative mutation of Pak1, and the other with constitutively
active Pak1, targeted to express in mammary glands by the beta-lactoglobulin promoter. The ectopic overexpression of
dominant negative Pak1 resulted in the developmental retardation of the mammary glands and poor functional differentiation
characterized by reduced milk production. The ectopic expression of constitutive active form of Pak1, on the other hand,
resulted in the hyperplasia of the mammary epithelium. We further analyzed the molecular mechanisms related and found
that Pak1 activates Stat5a, a critical transcription factor controlling mammary gland development and differentiation by
phosphorylation of Serine 729. Also, Pak1 activates estrogen receptor by phosphorylation at Serine 305. We further generated
an ER knockin mice with this phosphorylation site mutated and got an ER functionally compromised animal.
Rui-An Wang received his M.D degree from Nanfang Medical University, and his Ph.D degree from the 3
Military Medical University of China. He had been a
lecturer of histology for years and then did his postdoctoral training in USA, at M.D.Anderson Cancer Center and worked as a faculty there for eight years. His
scientific research experience has been very extensive, as in the field of endocrinology, male reproductive biology, developmental biology and cancer biology.
His publications include those high rank journals as Nature, Nature Cell Biology, EMBO J, JCB, PNAS, Oncogene, etc. He is now a professor of pathology of the
Fourth Military Medical University of China. What is special of him is that he proposed a new cancer theory, the stem cell misplacement theory, which posits that in
situ carcinoma is not cancer, nor the origin of invasive cancer. The invasive cancer grows out de novo in the stroma fromdislodged epithelial stem cells. Apoptosis,
instead of being a barrier of carcinogenesis as generally believed, stimulates carcinogenesis, cancer growth and metastasis.
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