Omomyc expression in skin prevents Myc-induced papillomatosis

Abstract

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 Mycdependent 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.

Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice

“…Primary antibodies were as follows: rabbit polyclonal anti-Omomyc [prepared in-house, Evan labora-tory (Soucek et al 2004)] and mouse monoclonal anti-p21 (clones SX118 and SXM30, BD Pharmingen). Primary antibodies were applied for 2 h in blocking buffer (2.5% BSA, 5% goat serum, 0.3% Triton X-100 in PBS), sections were washed, and speciesappropriate secondary Alexa fluor 488 dye-conjugated antibodies (Amersham) or Vectastain ABC kit and DAB reagents (Vector Laboratories) were applied.…”

“…Omomyc retains the ability to bind its physiological partner, Max, but also heterodimerizes with wild-type c-Myc, N-Myc, and L-Myc proteins. Since Myc:Omomyc heterodimers can no longer bind to the canonical Myc E-box CACGTG DNA recognition element, Omomyc overexpression inhibits Myc-dependent target gene transactivation (Soucek et al 2002(Soucek et al , 2004Savino et al 2011). Omomyc is therefore a competitive inhibitor of Myc transcriptional activation, and we used it to model pharmacological inhibition of Myc by generating mice (TREOmomyc) in which Omomyc expression is driven from a tetracycline-responsive promoter element.…”

Endogenous Myc maintains the tumor microenvironment

“…To address these questions directly, we combined the RIP1-Tag2 pancreatic b-cell mouse tumor model with our TRE-Omomyc;CMVrtTA mouse, in which the dominantnegative Myc inhibitor Omomyc (Soucek et al 1998(Soucek et al , 2002(Soucek et al , 2004 may be reversibly induced systemically in vivo (Soucek et al 2008). Omomyc competitively blocks Myc/Max heterodimerization and binding to the E-box, thus inhibiting the capacity of Myc proteins to transactivate target genes (Soucek et al 1998(Soucek et al , 2002.…”

Gerometabolites: The pseudohypoxic aging side of cancer oncometabolites

“…However, the development of the Myc-interfering molecule termed Omomyc, which binds c-and N-Myc, Max, and Miz-1 but does not bind Mad or certain HLH proteins, has demonstrated that it might cause edge-specific perturbations in the Myc interactome that destroy specific protein interactions of the Myc node while leaving others intact. [117][118][119][120][121][122][123] This results in a "rewriting" of the Myc transcriptome in a manner that produces opposing effects on the 2 arms of Myc activity, namely transactivation and transrepression of gene transcription. Specifically, Omomyc prevents Myc binding to promoter E-boxes and the transactivation of target genes while allowing Myc to retain Miz-1-dependent binding to promoters and transrepression function.…”