The nuclear transcription factor C/EBPalpha has an important role in the expression of genes regulating energy mtetbolism, in the differentiation and maturation of lung and adipose tissues, and in the acute phase, or inflammatory response as demonstrated in a knockout mouse model for C/EBPalpha generated in our laboratory. The long term goals of this application are to determine the molecular basis for the transcriptional regulation of acute phase genes in the newborn animal which our in vivo studies of the mutant mice show is dependent on expression of c/EBPalpha. We will examine several molecular mechanisms by which C/EPB alpha may regulate this primary inflammatory response in order to define C/EPB alpha 's role in this pathway.
The specific aims i nclude characterization of other transcription factors known to regulate the acute phase response to determine whether their activity is dependent on C/EBP alpha. Cytokine signaling pathways will be examined in the newborn animals to determine whether these responses are altered by the loss of C/EBP alpha expression. Finally, we will test whether mutations of the C/EBP alpha protein that lack the ability to heterodimierize and/or interact with NFkappaB will be able to restore the acute phase response in order to distinguish between the DNA molecular basis for altered C/EBPbeta mRNA translation I the absence of C/EBP alpha. These studies stem from the unexpected observation that the C/EBPbeta protein isoforms that result from multiple translation initiation start sites are very different in the livers of C/EBPalpha knockout newborns compared to the normal littermates. This observation reveals a new activity for C/EBPalpah; that of a regulator of C/EBPbeta mRNA translation initiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053045-03
Application #
2906098
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Haft, Carol R
Project Start
1997-08-28
Project End
2000-07-31
Budget Start
1999-08-16
Budget End
2000-07-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Singh, Pallavi; Goode, Triona; Dean, Adam et al. (2011) Elevated interferon gamma signaling contributes to impaired regeneration in the aged liver. J Gerontol A Biol Sci Med Sci 66:944-56
Singh, Pallavi; Coskun, Zeynep Z; Goode, Catriona et al. (2008) Lymphoid neogenesis and immune infiltration in aged liver. Hepatology 47:1680-90
Yoshida, Yuichi; Hughes, Douglas E; Rausa 3rd, Francisco M et al. (2006) C/EBPalpha and HNF6 protein complex formation stimulates HNF6-dependent transcription by CBP coactivator recruitment in HepG2 cells. Hepatology 43:276-86
Yang, Jianqi; Croniger, Colleen M; Lekstrom-Himes, Julie et al. (2005) Metabolic response of mice to a postnatal ablation of CCAAT/enhancer-binding protein alpha. J Biol Chem 280:38689-99
Mackey, Stephanie L; Darlington, Gretchen J (2004) CCAAT enhancer-binding protein alpha is required for interleukin-6 receptor alpha signaling in newborn hepatocytes. J Biol Chem 279:16206-13
Welm, Alana L; Timchenko, Nikolai A; Ono, Yasuko et al. (2002) C/EBPalpha is required for proteolytic cleavage of cyclin A by calpain 3 in myeloid precursor cells. J Biol Chem 277:33848-56
Welm, A L; Timchenko, N A; Darlington, G J (1999) C/EBPalpha regulates generation of C/EBPbeta isoforms through activation of specific proteolytic cleavage. Mol Cell Biol 19:1695-704
Darlington, G J (1999) Molecular mechanisms of liver development and differentiation. Curr Opin Cell Biol 11:678-82
Burgess-Beusse, B L; Timchenko, N A; Darlington, G J (1999) CCAAT/enhancer binding protein alpha (C/EBPalpha) is an important mediator of mouse C/EBPbeta protein isoform production. Hepatology 29:597-601
Burgess-Beusse, B L; Darlington, G J (1998) C/EBPalpha is critical for the neonatal acute-phase response to inflammation. Mol Cell Biol 18:7269-77