Makoto Senoo

Associate Professor, Department of Molecular & Cell Biology

  • Title Associate Professor, Department of Molecular & Cell Biology
  • Office 700 Albany St. W Bldg., W-202D, Boston, MA 02118 USA
  • Phone 617-638-4965

Overview

Stem cells are capable of self-renewal and differentiation into specialized cell types, and their use has emerged as a novel therapeutic treatment in regenerative medicine. Although the functions of various stem cells have been extensively studied, the specific factors and mechanisms that control stem cell fate are not well understood. The focus of Senoo laboratory is to understand the regulatory mechanisms of self-renewal and differentiation of epithelial stem cells, with a long-term goal of developing novel strategies for stem cell-directed therapeutic treatments of epithelial diseases.

DNE1Discovery of p63, the master regulator of epithelial stem cells.

We and others have identified the transcription factor p63 (variably referred to as KET, p51, p40 and p73L) with high sequence identity to the tumor suppressor p53 and its homolog p73. Our initial efforts involved investigating the potential role of p63 in human cancer. However, mutation of p63 is very rare and it does not appear to function as a classical tumor suppressor. Instead, we found that p63 is essential for the proliferative potential of epithelial stem cells. Since then, our research program has been dedicated to understanding the molecular basis of self-renewal and differentiation of epithelial stem cells.

DNE2Intrinsic mechanisms that regulate epithelial stem cell self-renewal.

p63 is expressed in stem cells in many different epithelia, such as the skin, teeth, cornea, prostate, and breast. Loss-of function mouse models for p63 have revealed a dramatic epithelial phenotype during embryogenesis, marked by the loss of these tissues. As such, p63 was among the first genes proposed to function in the maintenance of stem cell populations. However, function of p63 is not simple due to the existence of isoforms with growth suppressive functions (TAp63) as well as dominant negative isoforms with oncogenic properties (DNp63). Notably, the carboxy (C)-terminus of p63 is mutated or lost in patients with ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome and other ectodermal dysplasias (EDs), characterized by developmental abnormalities of ectodermal structures. Recently, by generating a novel mouse model, we found that p63 C-terminus regulates self-renewal of epithelial stem cells by balancing the TAp63 and DNp63 isoform functions. Deciphering gene programs mediated by the p63 C-terminus will provide significant insight into our understanding of physiology and pathogenesis of epithelia.

DNE3External cues that regulate epithelial stem cell self-renewal.

Stem cell function is intimately linked to extrinsic factors provided by the stem cell microenvironment, so called “stem cell niche.” Although epithelial stem cell niche has not been well characterized in vivo, many of its aspects are recapitulated in co-culture with 3T3-J2 cells, a system developed by Howard Green and colleagues in 1970’s. This co-culture has been used worldwide to regenerate skin grafts for the treatment of patients with massive full-thickness burns, and more recently for damaged corneas. By dissecting signaling pathways, we have revealed the existence of a uniquely configured mechanism in 3T3-J2 cells that optimizes support for epithelial stem cell self-renewal. Decoding “Green’s magic” will help us to develop novel strategies for manipulating external cues that regulate epithelial stem cell self-renewal in regenerative medicine.

Selected Publications

[1] Senoo M, Seki N, Ohira M, Sugano S, Watanabe M, Inuzuka S, Okamoto T, Tachibana M, Tanaka T, Shinkai Y, Kato H. A Second p53-related protein, p73L, with high homology to p73. Biochem Biophys Res Commun (1998) 248: 603-607.

[2] Senoo M, Tsuchiya I, Matsumura Y, Mori T, Saito Y, Kato H, Okamoto T, Habu S. Transcriptional dysregulation of the p73L/p63/p51/p40/KET gene in human squamous cell carcinomas: expression of DNp73L, a novel dominant-negative isoform, and loss of expression of the potential tumor suppressor p51. British J Cancer (2001) 84: 1235-1241.

[3] Nishi H, Senoo M, Nishi KH, Murphy B, Rikiyama T, Matsumura Y, Habu S, Johnson AC. p53 homolog p63 represses epidermal growth factor receptor expression. J Biol Chem (2001) 276: 41717-41724.

[4] Senoo M, Matsumura Y, Habu S. TAp63g (p51A) and DNp63a (p73L), two major isoforms of the p63 gene, exert opposite effects on the vascular endothelial growth factor (VEGF) gene expression. Oncogene (2002) 21: 2455-2465.

[5] Senoo M, Manis JP, Alt FW, McKeon F. p63 and p73 are not required for the development and p53-dependent apoptosis of T cells. Cancer Cell (2004) 6: 85-89.

[6] Senoo M, Pinto F, Crum CP, McKeon F. p63 is essential for the proliferative potential of stem cells in stratified epithelia. Cell (2007) 129: 523-536.

[7] Suzuki D, Senoo M. Increased p63 phosphorylation marks early transition of epidermal stem cells to progenitors. J Inv Dermatol (2012) 132: 2461-2464.

[8] Suzuki D, Sahu R, Leu NA, Senoo M. The carboxy-terminus of p63 links cell cycle control and the proliferative potential of epidermal progenitor cells. Development (2015) 142: 282-290.

[9] Suzuki D, Senoo M. Dact1 regulates the ability of 3T3-J2 cells to support proliferation of human epidermal keratinocytes. J Inv Dermatol (2015) 135: 2894-2897.

Departments
Molecular & Cell Biology
Affiliations
Faculty

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