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Accueil > Bibliographie > Inactivation of transcription factor Pit-1 to target tumoral (...)

Inactivation of transcription factor Pit-1 to target (...)

Hum Gene Ther. 2012 Jan ;23(1):104-14
Inactivation of transcription factor Pit-1 to target tumoral somato-lactotroph cells.
Roche C, Rasolonjanahary R, Thirion S, Goddard I, Fusco A, Figarella-Branger D, Dufour H, Brue T, Franc JL, Enjalbert A, Barlier A.

The treatment of growth Hormone(GH) and prolactin (PRL) secreting tumors resistant to current therapeutic molecules (somatostatin and dopamine analogs) remains challenging. To target these tumors specifically, we choose to inactivate a gene coding for a crucial factor in cell proliferation and in hormonal regulation, specifically expressed in pituitary, using a dominant-negative form of this gene involved in human pituitary deficiencies : transcription factor Pit-1 (POU1-F1) mutated on arginine 271 to tryptophan (R271W). After lentiviral transfer, the effect of R271W was studied in vitro on human tumoral somatotroph and lactotroph cells and on murine mammosomatotroph cell line GH4C1 and in vivo on GH4C1 subcutaneous xenografts in nude mice. R271W induced a decrease in GH and PRL hypersecretion by controlling the transcription of the corresponding hormones. This mutant decreased cell viability by an apoptotic mechanism and in vivo blocked the tumoral growth and GH secretion of xenografts obtained after transplantation of GH4C1 expressing mutant R271W. The strategy of using a dominant-negative form of a main factor controlling cell proliferation and hormonal secretion, and exclusively expressed in pituitary, seems promising for gene therapy of human pituitary tumors and may be translated to other types of tumors maintaining some differentiation features.

PubMed

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