Pituitary tumor transforming gene (PTTG) carboxy-terminal peptides and methods of use thereof to inhibit neoplastic cellular proliferation and/or transformation
Disclosed is a method of inhibiting neoplastic cellular proliferation and/or transformation of mammalian cells, including cells of human origin, in vitro or in vivo. The inventive method involves the use of a composition containing a pituitary tumor transforming gene carboxy-terminal peptide (PTTG-C), which can be comprised in a chimeric protein, which has the ability to regulate endogenous pituitary tumor transforming gene (PTTG) expression and/or function in a dominant negative manner. Kits comprising the inventive compositions are also disclosed for the treatment of neoplastic cellular proliferation in vitro or in vivo. Isolated PTTG-C peptides and PTTG-C-containing chimeric proteins are described.
1. A method of inhibiting neoplastic cellular proliferation and/or transformation of a cell of mammalian origin comprising:
delivering to a mammalian cell that expresses PTTG a composition comprising a PTTG-C peptide consisting of SEQ ID NO: 9,
complexed with a cellular uptake-enhancing agent, in an amount and under conditions sufficient to enter the cell, whereby neoplastic cellular proliferation and/or frame formation of the cell is inhibited.
2. The method of claim 1 , wherein the cell is of human origin.
3. The method of claim 1 , wherein the cell exhibits neoplastic, hyperplastic, cytologically dysplastic, or premalignant cellular growth or proliferation.
4. The method of claim 1 , wherein the cell is a malignant cell.
5. The method of claim 1 , wherein the composition is delivered to the cell in vitro.
6. The method of claim 1 , further comprising administering the composition to a mammalian subject, such that the PTTG-C peptide is delivered to the cell in vivo.
7. The method of claim 1 , wherein said uptake enhancing agent comprises a polycationic lipid.
8. The method of claim 1 , wherein said uptake enhancing age t comprises a cellular uptake-enhancing and/or importation-competent peptide segment.
9. The method of claim 8 , wherein the cellular uptake-enhancing and/or importation-competent peptide segment is a human immunodeficiency virus TAT-derived peptide segment or a signal peptide from Kaposi fibroblast growth factor.
10. An isolated protein, consisting of:
a PTTG carboxy-terminal peptide consisting of SEQ ID NO:9.
11. A composition for inhibiting neoplastic cellular proliferation and/or transformation in a cell that expresses PTTG, comprising the protein of claim 10 and a pharmaceutically acceptable carrier.
12. The composition of claim 11 , further comprising a cellular uptake-enhancing agent complexed with said PTTG carboxy-terminal peptide.
13. The composition of claim 11 , wherein said uptake enhancing agent comprises a lipid agent.
14. The composition of claim 12 , wherein said uptake enhancing agent comprises a polycationic lipid agent.
15. The composition of claim 12 , wherein said uptake enhancing agent comprises a cellular uptake-enhancing and/or importation-competent peptide segment.
16. The composition of claim 15 , wherein the cellular uptake-enhancing and/or importation-competent peptide segment is a human immunodeficiency virus TAT-derived peptide segment or a signal peptide from Kaposi fibroblast growth factor.
17. A chimeric protein, consisting of:
(i) a first segment consisting of a PTTG carboxy-terminal peptide consisting of SEQ ID NO:9; and
(ii) a second segment, which is a cellular uptake-enhancing and/or importation-competent peptide segment.
18. A composition for inhibiting neoplastic cellular proliferation and/or transformation in a cell that expresses PTTG, comprising the chimeric protein of claim 17 and a pharmaceutically acceptable carrier.
19. The composition of claim 18 , wherein the cellular uptake-enhancing and/or importation-competent peptide segment is a human immunodeficiency virus TAT-derived peptide segment or a signal peptide from Kaposi fibroblast growth factor.
20. A kit for the treatment of neoplastic cellular proliferation in cells that express PTTG, said kit comprising:
the composition of claim 11 ; and
instructions for the use of said composition for inhibiting neoplastic cellular proliferation and/or transformation in cells that express PTTG.
21. A kit for the treatment of neoplastic cellular proliferation in cells that express PTTG, said kit comprising:
the composition of claim 15 ; and
instructions for the use of said composition for inhibiting neoplastic cellular proliferation and/or transformation in cells that express PTTG.
22. A kit for the treatment of neoplastic cellular proliferation in cells that express PTTG, said kit comprising:
the composition of claim 18 ; and
instructions for the use of said composition for inhibiting neoplastic cellular proliferation and/or transformation in cells that express PTTG.