Omomyc expression in skin prevents Myc-induced papillomatosis.
Obligate sensitization to apoptosis provides a safeguard mechanism against the oncogenic potential of Myc. Omomyc is a mutant bHLHZip domain that sequesters Myc in complexes that are unable to bind to the E box recognition element and activate transcription but remain competent for transcriptional repression. Omomyc has the peculiar properties of reverting Myc-induced transformation of tissue culture cells and enhancing Myc proapoptotic function. Thus, Omomyc has the potential to act as a potent suppressor of Myc-induced oncogenesis. To validate the therapeutic potential of Omomyc in vivo, we targeted its expression to the adult suprabasal epidermis of Inv-c-MycER (TAM) transgenic mice which express a switchable form of the Myc protein in suprabasal cells. Activation of Myc induces rapid epidermal hyperplasia and papillomatosis. We show that Omomyc inhibits such Myc-induced papillomatosis, potentiating Myc-dependent apoptosis in a tissue in which it is usually strongly suppressed. Furthermore, Omomyc expression restores the normal keratinocyte differentiation program and skin architecture, both of which are otherwise disrupted by Myc activation. These findings indicate that it is possible to selectively enhance the intrinsic apoptotic pathway mediated by Myc and so quell its oncogenic action.
Soucek
L
L
Cancer Research Institute, UCSF, San Francisco, CA 94143-0875, USA. lsoucek@cc.ucsf.edu
Nasi
S
S
Evan
G I
GI
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004817:Epidermis / Q000378:metabolism; D005434:Flow Cytometry; D005822:Genetic Vectors; D006801:Humans; D006915:Hydroxytestosterones / Q000494:pharmacology; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D010212:Papilloma / Q000378:metabolism* / Q000517:prevention & control*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D051381:Rats; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000517:prevention & control*; D013997:Time Factors; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C494813:Bcl2l1 protein, rat; D006915:Hydroxytestosterones; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; C032278:4,17 beta-dihydroxy-4-androstene-3-one