Copy - FOXA1 TRANSCRIPTION FACTOR
Heritage A
Created on November 20, 2022
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Transcript
BY HERITAGE AFOLABI
FOX A1TRANSCRIPTION FACTOR
INDEX
6. Possible treatment
5. Experiments !
4. Development in Mice
3. ER FOX A1 COMPLEX
2. What is FOXA1 ?
1. Family History
James E. Darnell
A LITTLE FAMILY HISTORY...
- 90s- was trying to find transcription factors responsible for the tissue specific expression of genes defining liver developemnt and function
- Discovered HNF-3A
- Expression was enriched in liver tissue
- was essential for liver Morphogenesis
Arround the same time..
- Drisophila Forkhead (fkh) gene sequence was determined
- essential for Drisophila development - Detlef Weigal
- High homology with hnf3a bidning domain discovered after aligning DNA
- lack zinc finger motifs- new class of transcription factors
- AKA hepatocyte nuclear factor 3-alpha
- Member of Forkhead box (FOX) protein family
- Acts as a Pioneer factor for many receptors
- Promotes endocrine-resistant cell growth (breast cells)
- regulates a variety of tissues during embryogenesis and early life
What is FOX A1 ?
ER FOXA1 COMPLEX
- FOXA1 opens consenced chomatin
- ER binds at enhancer
- Chromatin loop forms to bring ER within close proximetry
- Transcription of growth promoting associated genes
Image depicting different stages of muce embryogenesis
- FOXA1 RNA detected in the late primative streak stage in midline endodorm
- Later on in ventral floor plate, notochord and gut
- In adults- mesoderm and ectroderm derived tissues
- Evidence for role in developmental specification
FOXA1 IN DEVELOPMENT IN MICE
- immunostained embryos with antibody for FOXA1
- liver stomach lung, dorsal epethelium of tongue
- Prove secfifcity of antibodies
- HeLA cell Lycates transfected with pcDNA3.1 or
- FOX A2 done with rat cDNA
- subjected to electrophresis
- immunoblotted with respective antibodies
- no reaction cross over
- detected FOXa1 and reactive fragment (Mr-25000)
- detected FOXa2 and reactive frgment
immunohistochemical localisation of foxa1
Use mammary gland transplantation processes instead
At birth, is similar to wild type but dies soon after due to hypoglycemia and dehydration
New method
Stage 2
mice embryo has homozygous deletion of FOXa1
Stage 1
impact of FOXA1 on mammary gland morphogenesis
- Many women who have ER related breast cancer become resistant to ER targetting medication
- need to create treatment that targets the ER complex as a whole
- FOXA1 a very important target for medicines as the complex cannot work without it
- Opportunity for new effective drugs
POSSIBLE TREATMENT
[1]G. M. Bernardo and R. A. Keri, “FOXA1: a transcription factor with parallel functions in development and cancer,” Bioscience Reports, vol. 32, no. 2, pp. 113–130, Oct. 2011, doi: 10.1042/bsr20110046.[2]X. Fu, R. Pereira, C. De Angelis, and J. Veeraraghavan, “FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer,” PNAS, vol. 116, no. 52, pp. 1–2, Nov. 2019, Accessed: Nov. 15, 2022. [Online]. Available: https://www.pnas.org/doi/suppl/10.1073/pnas.1911584116[3]D. D. Seachrist, L. J. Anstine, and R. A. Keri, “FOXA1: A Pioneer of Nuclear Receptor Action in Breast Cancer,” Cancers, vol. 13, no. 20, p. 3, Oct. 2021, doi: 10.3390/cancers13205205.[4]V. Besnard, S. E. Wert, W. M. Hull, and J. A. Whitsett, “Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues,” Gene Expression Patterns, vol. 5, no. 2, pp. 195–197, Dec. 2004, doi: 10.1016/j.modgep.2004.08.006.[5]P. P.L Tam and R. R Behringer, “Mouse gastrulation: the formation of a mammalian body plan,” Mechanisms of Development, vol. 68, no. 1–2, p. 6, Nov. 1997, doi: 10.1016/S0925-4773(97)00123-8.
Refrences
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