Method of modulating HSF-1
The present invention is directed to methods of modulating HSF1 activity comprising modifying the acetylation of the DNA binding domain of the HSF1.
1. A method of modulating the activity of heat shock transcription factor 1 (HSF1) in a human cell comprising modifying acetylation of a lysine residue in the DNA binding domain of the HSF1, wherein the lysine residue is lysine 80 (HSF1 K80).
2. The method of claim 1 , wherein the activity of HSF1 is increased by inhibiting the acetylation of the lysine residue.
3. The method of claim 1 , wherein the activity of HSF1 is decreased by promoting the acetylation of the lysine residue.
4. The method of claim 2 , wherein the acetylation of HSF1 K80 is inhibited by administering to the cell an effective amount an agent that inhibits acetylation of HSF1 K80, wherein the agent is selected from the group consisting of an isolated sirtuin, a sirtuin activating agent and a histone acetyltransferase (HAT) inhibiting agent.
5. The method of claim 4 , wherein the isolated sirtuin is sirtuin 1 (SIRT1).
6. The method of claim 4 , wherein a SIRT1 activating agent is administered.
7. The method of claim 4 , wherein a HAT inhibiting agent is administered.
8. The method of claim 3 , wherein the acetylation of HSF1 K80 is promoted by administering to the cell an agent that promotes acetylation of HSF1 K80, wherein the agent is selected from the group consisting of a sirtuin inhibiting agent and a HAT activating agent.
9. The method of claim 8 , wherein a SIRT1 inhibiting agent is administered.
10. The method of claim 9 , wherein the SIRT1 inhibiting agent is a small molecule, nucleic acid or antibody.
11. A method of increasing the activity of HSF1 in a subject in need thereof comprising inhibiting the acetylation of a lysine residue in the DNA binding domain of the HSF1 in a cell of said subject, wherein the lysine residue is HSF1 K80 or a corresponding conserved lysine residue.
12. The method of claim 11 , wherein an agent that inhibits the acetylation of HSF1 K80 is administered to said subject in an effective amount.
13. The method of claim 12 , wherein the agent that inhibits the acetylation of HSF1 K80 is an isolated sirtuin, a sirtuin activating agent or a HAT inhibiting agent.
14. The method of claim 11 , wherein the subject is a human.
15. The method of claim 14 , wherein a SIRT1 activating agent is administered.
16. The method of claim 14 , wherein a HAT inhibiting agent is administered.
17. A method of decreasing the activity of HSF1 in a subject in need thereof comprising promoting the acetylation of a lysine residue in the DNA binding domain of HSF1 in a cell of said subject, wherein the lysine residue is HSF1 K80.
18. The method of claim 17 , wherein an agent that promotes acetylation of HSF1 K80 or the corresponding conserved lysine residue is administered to said subject.
19. The method of claim 18 , wherein the acetylation of HSF1 K80 is promoted by administering to said subject a sirtuin inhibiting agent or a HAT activating agent.
20. The method of claim 19 , wherein the sirtuin inhibiting agent is a SIRT1 inhibiting agent.
21. The method of claim 17 , wherein the subject is a human.