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Center for Cancer Research, National Cancer Institute, National Institutes of Health


picture of Dr. Shioko Kimura

Shioko Kimura, Ph.D.


Head, Endocrinology Section
Laboratory of Metabolism
Center for Cancer Research
National Cancer Institute
National Institutes of Health
37 Convent Dr.
Bldg. 37, Rm. 2B15A
Bethesda, MD 20892
Phone:  301-496-0958
Fax:  301-496-8419
e-mail: shioko@helix.nih.gov

Shioko Kimura obtained her Ph.D. in chemistry in 1979 at Hokkaido University , Sapporo, Japan. After 3 years of post-doctoral study at Queen's University, Kingston, Ontario, Canada, she joined the National Institute of Child Health and Human Development as a visiting fellow. In 1986, she moved to the Laboratory of Molecular Carcinogenesis, National Cancer Institute. In 1996, she became a head of the Endocrinology Section in the Laboratory of Metabolism, National Cancer Institute.

RESEARCH

Thyroid hormone synthesis and thyroid development:

Our research interest is to understand the mechanisms of differentiation and maintenance of homeostasis of the thyroid and lung. Particularly, current efforts are focused on understanding the role of the thyroid-specific enhancer-binding protein (T/EBP) in transcription, physiology, and development. T/EPB is a homeodomain transcription factor that regulates expression of thyroid and lung-specific genes, including those encoding thyroid peroxidase, thyroglobulin, TSH receptor, and the Na/I symporter in the thyroid, and surfactant proteins A, B, and C, and clara cell secretary protein in the lung. T/EBP is expressed in the thyroid, lung, and ventral forebrain during early embryogenesis, suggesting that T/EBP may play a role in genesis of these organs. A mouse lacking T/EBP expression is missing the thyroid and pituitary and has severe defects in lung and hypothalamus. The establishment of a T/ebp-null mouse line unequivocally demonstrated that T/EBP is essential during development and provides an excellent animal model to study how the lung, thyroid, pituitary, and hypothalamus are formed during development.

Based on the detailed analyses of the defects in each organ, T/EBP appears to qualify as one of the master regulatory genes involved in morphogenesis of the thyroid, lung, and pituitary, which either activates or suppresses downstream target genes, ultimately leading to organ development. Our efforts have focused on identifying genes that are regulated by T/EBP during mammalian development and that are involved in organogenesis. To this end, we have carried out PCR-based subtraction library screening and microarray analysis using lungs obtained from wild-type and T/ebp-null mouse embryos. Several genes have been characterized that are expressed under the control of T/EBP in the lung during development. Efforts are also ongoing to produce and characterize a conditional T/ebp gene knock-out mouse line using the Cre-Lox P system that deletes T/EBP only in the thyroid or lung, in order to study physiological functions of T/EBP in these organs in relation to genesis, homeostasis and diseases.

Uteroglobin-related protein (UGRP)

Another research project is to characterize Uteroglobin-related protein (UGRP) 1 originally identified as a T/EBP downstream target gene that is highly expressed in the epithelial cells of the trachea, bronchus and bronchioles. Preliminary results suggest that UGRP1 may play a role in lung inflammation. In order to address this question, we are in process of producing UGRP1 conditional knockout mouse that specifically deletes UGRP1 only in lung and transgenic mouse that over-expresses UGRP1 in lung epithelial cells. These mice will be subjected to experimental allergic inflammation model where the effect of loss or gain of UGRP1 on the inflammatory status will be examined.


 
Representative Publications:
  1. Kikkawa, F., Gonzalez, F.J., and Kimura, S.: Characterization of a thyroid-specific enhancer located 5.5 kilobase pairs upstream of the human thyroid peroxidase gene. Mol. Cell. Biol. 10: 6216-6224, 1990.
  2. Mizuno, K., Gonzalez, F.J., and Kimura, S.: Thyroid-specific enhancer binding protein (T/EBP): cDNA cloning, functional characterization, and structural identity with thyroid transcription factor TTF-1. Mol. Cell. Biol. 11: 4927-4933, 1991.
  3. Kimura, S., Hara, Y., Pineau, T., Fernandez-Salguero, P., Fox, C.H., Ward, J.M., and Gonzalez, F.J.: The T/ebp null mouse: Thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes & Dev. 10: 60-69, 1996.
  4. Kimura, S.: Thyroid-specific enhancer-binding protein: Role in thyroid and organogenesis. Trends Endocrinol. Metab. 7: 247-252, 1996.
  5. Kimura, S.: Role of the thyroid-specific enhancer-binding protein (T/EBP) in transcription, development , and differentiation. Eur. J. Endocrinol. 136: 128-136, 1997.
  6. Oguchi, H. and Kimura, S.: Multiple transcripts encoded by the thyroid-specific enhancer-binding protein (T/EBP) / thyroid-specific transcription factor-1 (TTF-1) gene: Evidence of auto-regulation. Endocrinology 139: 1999-2006, 1998.
  7. Takuma, N., Sheng, H.Z., Furuta, Y., Ward, J.M., Sharma, K., Hogan, B.L.M., Pfaff, S.L., Westphal, H., Kimura, S., and Mahon, K.A.: Formation of Rathke's pouch requires dual induction from the diencephalon. Development 125: 4835-4840, 1998.
  8. Minoo, P., Su, G., Drum, H., Bringas, P., and Kimura, S.: Defects in tracheo-esophageal and lung morphogenesis in Nkx2.1(-/-) mouse embryos. Dev. Biol. 209: 60-71, 1999.
  9. Kimura, S., Ward, J.M., Minoo, P.: Thyroid-specific enhancer-binding protein (T/EBP) / thyroid transcription factor 1 (TTF1) is not required for the initial specification of the thyroid and lung primordia. Biochimie 81: 321-327, 1999.
  10. Sussel, L., Marin, O., Kimura, S., and Rubenstein, J.: Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. Development 126: 3359-3370, 1999.
  11. Yuan, B., Kimura, S., Englehardt, T.T., Smith, B.R., and Minoo, P.: Inhibition of distal lung morphogenesis in Nkx2,1(-/-) embryosDev. Dyn. 217:  180-190, 2000.
  12. Ueno, T., Tamura, S., Frels, W.I., Shou, M., Gonzalez, F.J., and Kimura, S.: A transgenic mouse expressing human CYP1A2 in the pancreas. Biochem. Pharm. 60: 857-863, 2000.
  13. Kimura, S. and Gonzalez, F.J.: Applications of genetically manipulated mice in pharmacogenetics and pharmacogenomics. Pharmacology 61: 147-153, 2000.
  14. Corchero, J., Pimprale, S., Kimura, S., and Gonzalez, F.J.: Organization of the CYP1A2 cluster on human chromosome 15: Implications for gene regulation. Pharmacogenetics 10: 1-6, 2000.
  15. Moeller, L.C., Kimura, S., Kusakabe, T., Liao, X.-H. Refetoff, S.: Hypothyroidism in thyroid transcription factor 1 haploinsufficiency is caused by reduced expression of the thyroid stimulating hormone receptor. Mol. Endocrinol. 17: 2295-2302, 2003.

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