Professor of Cell and Developmental Biology*
*And Faculty Scientist, Lawrence Berkeley National Laboratory, Division of Life Sciences
- We are interested in the signal transduction pathways that regulate development and cancer. We employ in vitro mechanistic studies in tissue culture cells in combination with biological analyses using in vivo mouse models to understand how disruption of the normal signaling network leads to developmental defects and human cancer.
Currently, we focus on several important tumor suppressor pathways that also play important roles in regulating tissue development and homeostasis, including pathways downstream of the TGFβ family of cytokines, p53 and Hippo pathway.
The TGFβ family of cytokines, including TGFβs, Nodal, activins and BMPs, plays important roles in development, tumor development and progression as well as epithelial-stromal interaction. They exert diverse effects through the cell surface receptors and downstream Smad proteins. The Smad proteins are transcription factors that upon phosphorylation by the receptor kinases, accumulate in the nucleus and regulate the expression of target genes. The activity of the Smad proteins is subjected to regulation by various cellular co-factors. SnoN and the related Ski proteins are critical negative modulators of the Smads by binding to and repressing their transcription activities. SnoN and Ski play important and complex roles in human cancer and embryonic development. In many types of human cancer including breast cancer, lung cancer, esophageal, lymphoma, colon cancer and melanoma, their expression was deregulated. We have shown recently that these proteins possess both oncogenic and tumor suppressor activities by regulating the proliferation, survival and senescence of cells. In addition to modulating TGFβ signaling, SnoN can also activate the p53 pathway in response to various cellular stress signals, through which it regulates aging, tumor progression and tissue regeneration.
We are interested in understanding the functions of SnoN and Ski and how they coordinate the actions of various signaling pathways, in tumorigenesis, development and ageing using both tissue culture cell lines and mouse models. Our current research focused on the following areas:
The role of TGFβ signaling/SnoN in mammary stem cell regulation and breast cancer In adult mammary gland, mammary epithelial cells undergo massive proliferation and differentiation during pregnancy and lactation to produce and secrete milk. Recent studies suggest that a group of luminal progenitor cells may give rise to alveolar and ductal epithelial cells that are crucial for these processes. Interestingly, the molecular signature of this luminal progenitor population is highly similar to that of the most aggressive basal breast cancer subtype, suggesting that these luminal progenitor cells may be the originals of these basal breast cancer. Thus, understanding how luminal progenitor cells are regulated and maintained is critical not only for understanding normal mammary gland function but also for the development and progression of breast cancer. Using a knockout mouse model, we recently showed that SnoN plays a critical role in the generation and differentiation of alveolar epithelial cells and is essential for the onset of lactation. Using this mouse model and in combination with a three-dimensional matrigel culture (3D) model, we are dissecting how SnoN co-ordinates TGFβ and prolactin signaling to regulate the expansion, maintenance and differentiation of luminal progenitor cells, and how disruption of this process leads to breast cancer.
Role of SnoN in regulation of aging and adipose tissue development We recently showed that mice expressing a mutant SnoN defective in antagonizing TGFß signaling exhibited premature aging with a shortened life span, decreased reproductivity, osteoporosis and reduced regenerative capacity, as well as resistance to tumorigenesis, similar to that found in mice expressing an active p53. Subsequently we found that indeed, SnoN can activate p53 in response to cellular stress signals to promote cell senescence and tumor suppression. In addition, these mice also displayed a markedly reduced subcutaneous adipose tissue. By combining phenotype analysis in vivo with biochemical studies in in vitro preadipocyte differentiation models, we are determining the signaling mechanisms by which SnoN regulates adipocyte differentiation.
Regulation of Hippo signaling by SnoN/Ski during breast cancer progression Hippo pathway has recently been shown to regulate cell contact inhibition, organ size and cancer progression. Ski and SnoN appear to be important regulators of this pathway, in particularly, the activity of the TAZ/YAP proteins. Through this regulation, they modulate the epithelial to mesenchymal transdifferentiaion of breast cancer cells and the self-renewal activity of breast cancer stem cells. We are investigating these regulatory mechanisms.
SnoN activates p53 directly to regulate aging and tumorigenesis. [Pan, D., Zhu, Q. Conboy, M.J., Conboy, I.M., and Luo, K. (2012) Aging Cell. In press.]
SnoN regulates mammary gland morphogenesis and lactation by promoting prolactin/ STAT5 signaling. [Jahchan N.S., Wang, D., Bissell, M.J., and Luo K. (2012) Development 139: 3147-3156.]
Transforming growth factor-beta regulator SnoN modulates mammary gland branching morphogenesis, postlactational involution, and mammary tumorigenesis. [Jahchan NS, You YH, Muller WJ, and Luo K. (2010)Cancer Res. 70: 4204-13.]
SnoN functions as a tumor suppressor by inducing premature senescence. [Pan, D., Zhu, Q. and Luo, K. (2009)EMBO J. 28: 3500-3513.]
TGF-β suppresses the ability of Ski to inhibit tumor metastasis by inducing its degradation. [Le Scolan, E., Zhu, Q., Wang, L., Bandyopadhyay, A., Javelaud, D., Mauviel, A., Sun, L., Luo, K. (2008) Cancer Res. 68: 3277-3285.]
Dual Role of SnoN in mammalian tumorigenesis. [Zhu, Q., Krakowski, A.R., Dunham, E.E., Wang, L., Bandyopadhyoay, A., Berdeaux, R., Martin, G.S., Sun, L., and Luo, K. (2007) Mol Cell Biol. 27: 324-39.]
Cytoplasmic SnoN in normal cells and non-malignant tissues antagonizes TGFβ signaling through sequestration of the Smad proteins. [A.R. Krakowski, J. Laboureau, A. Mauviel,M.J. Bissell, and K. Luo (2005) Proc. Natl. Acad. Sci. 102: 12437-12442.]Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: Insights on Ski-mediated repression of TGF-β signaling. [J.-W. Wu, A. R. Krawitz, J. Chai, W. Li, F. Zhang, K. Luo and Y. Shi (2002) Cell 110, 357-367.]
Ski represses BMP signaling to induce neural cell fate. [W. Wang, F. V. Mariani, R. M. Harland and K. Luo (2000) Proc. Natl. Acad. Sci. 97, 14394-14399]
Negative feedback regulation of TGFβ signaling by the SnoN oncoprotein. [S. L. Stroschein, W. Wang, S. Zhou, Q. Zhou, and K. Luo (1999) Science 286, 771-774]
Last Updated 2009-08-03