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 two important tumor suppressor pathways that also play important roles in regulating tissue development and homeostasis, the transforming growth factor-β (TGFβ)/Smad pathway and Hippo pathway. Since all intracellular signaling pathways eventually converge on the transcription machinery, and recent studies have shown that many developmental and growth regulatory genes are controled predominantly at the step of transcription elongation, we also investigate the specific function of various transcription elongation complexes in breast cancer progression.
The TGFβ family of cytokines, functioning through the Smad proteins, plays important roles in vertebrate development, carcinogenesis and malignant progression as well as epithelial-stromal interaction. 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 embryonic development and 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. More recently we show that both Ski and SnoN are important regulators of the Hippo pathway.
We are interested in understanding the functions of SnoN and Ski and how they coordinate the actions of various signaling pathways, in various aspects of development and in tumorigenesis using a combination of tissue culture cell lines, three-dimentional cutlure models and in vivo 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, prolactin and Hippo 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. We hypothesize that SnoN relays the signals from the cell polarity complexes to coordinate the activity of various intracellular signaling pathways. In breast cancer cells, this signaling crosstalk regulates the expansion of breast cancer stem cells and tumor progression. We are investigating these regulatory mechanisms.
Function of the P-TEFb transcription elongation complexes in breast cancer progression The positive transcription elongation factor b (P-TEFb) stimulates transcriptional elongation by phosphorylating Pol II and antagonizing negative elongation factors. In cells, P-TEFb exists in three complexes: the inhibitory 7SK snRNP that functions as a reservoir of P-TEFb, the active Brd4 complex and the super elongation complex (SEC). We recently showed that P-TEFb activity is important for the epithelial-mesenchymal transition (EMT) and plays a key role in promoting breast cancer progression by directly controlling the expression of upstream EMT and metastasis regulators. We are investigating how a general transcription complex exerts specific functions in promoting breast cancer EMT and metastasis.
Ski as a novel regulator of Hippo signaling and TAZ to suppress breast cancer progression. [Rashidian, J., Le Scolan, E., Ji, X., Nomura, D., and Luo, K. (2015) Science Signal. 8, ra14].
LARP7 suppresses P-TEFb activity to inhibit breast cancer progression and metastasis. [Ji, X., Lu, H., Zhou, Q., and Luo, K. (2014) Elife. Jul 22; 3:e02907. doi: 10.7554/eLife.02907.]
Positive role of SnoN in regulating TGFb/ Smad1/5 signaling during embryonic angiogenesis. [Zhu, Q. and Luo, K. (2013) J. Cell. Biol. 202(6): 937-50.]
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.]
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. 11: 920-911.]
SnoN functions as a tumor suppressor by inducing premature senescence. [Pan, D., Zhu, Q. and Luo, K. (2009) EMBO J. 28: 3500-3513.]
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]
Photo credit: Mark Joseph Hanson of Mark Joseph Studio.
Last Updated 2015-08-27