P450RAI-2 (P450 cytochrome 26B), encoding nucleic acid molecules and methods and uses thereof
The present invention provides a novel all-trans-RA inducible all-trans-RA metabolizing cytochrome P450, P450RAI-2, that is predominantly expressed in the brain, cerebellum in particular. It is also expressed in normal and tumour lung tissue and in breast cancer cells and may have a correlation with lung and breast cancer. Human P450RAI-2 show 42% amino acid identity to human P450RAI-1 and when transfected into COS-1 cells causes the rapid conversion of all-trans-RA into more polar metabolites including the inactive products 4-oxo-RA, 4-OH-RA and 18-OH-RA. P450RAI-2, as with P450RAI-1, is also inducible in certain cultured cell lines exposed to all-trans-RA. Methods for and uses of the new polynucleotide, polypeptide, fragments thereof and inhibitors thereof, include the treatment of dermatological disorders, cancer and certain brain disorders.
1. A method for inhibiting P450RAI-2 induced retinoic acid hydroxylation in an organism or in an in vitro system comprising administering to the organism or the in vitro system an effective amount of an antisense nucleic acid or oligonucleotide substantially complementary to at least a portion of the sequence identified as SEQ ID NO:4.
2. The method of claim 1 wherein the portion is at least 5 bases in length, or at least about 10 bases in length, or at least about 15 bases in length, or at least about 20 bases in length, or at least about 25 bases in length, or at least about 30 bases in length, or at least about 35 bases in length, or at least about 40 bases in length, or at least about 45 bases in length, or at least about 50 bases in length.
3. The method of claim 1 wherein the organism is human.
4. The method of claim 1 wherein the organism is being treated for a disease selected from the group consisting of cancer, actinic keratosis, oral leukoplakia, a secondary tumor of the head and/or neck, a non-small cell lung carcinoma, a basal cell carcinoma, acute promyelocytic leukemia, skin cancer, and a premalignancy associated actinic keratosis, acne, psoriasis and/or ichthyosis.
5. The method of claim 4 wherein the disease is acute promyclocytic leukemia.
6. The method of claim 4 wherein the disease is lung cancer.
7. The method of claim 6 wherein the lung cancer is non-small cell lung cancer.