Myc, cell competition, and compensatory proliferation

The proto-oncogene Myc is already known to affect many cellular processes, but recent experiments in the fruit fly Drosophila melanogaster have revealed yet a new facet of Myc. Neighboring cells were shown to compare their Myc levels and the losers (cells with lower Myc activity) were actively eliminated. This phenomenon is called "cell competition," and it seems to be part of a developmental size and quality control program. Subversion of this mechanism may contribute to the transforming powers of Myc and possibly other oncogenes.     

Selective activation of apoptosis by a novel set of 4-aryl-3-(3-aryl-1-oxo-2-propenyl)-2(1H)-quinolinones through a Myc-dependent pathway

Oncogene addiction due to Myc deregulation has been identified in a variety of tumor types. In order to identify pharmacological agents that cause selective apoptosis in tumors with deregulated Myc expression, we designed a cell-based screening assay based on our Anti-cancer Screening Apoptosis Program (ASAP) technology targeting increased activity in a “Myc-addicted” cancer cell panel. We have identified a novel set of substituted 4-aryl-3-(3-aryl-1-oxo-2-propenyl)-2(1H)-quinolinones that activates apoptosis in cancer cell lines with deregulated Myc, but show low activity in cell lines where Myc is not deregulated. Apoptosis induced by these compounds is rapid, and is associated with a significant downregulation of Myc protein. Selective knockdown of Myc levels in these cells by RNA interference increased sensitivity to apoptosis with compound treatment. By targeting the Myc pathway in Myc-addicted cancer cells, we have identified a novel class of apoptotic inducers that selectively and efficiently target cancer cells with deregulated Myc.     

PML4 induces differentiation by Myc destabilization

Opposing functions like oncogene and tumor suppressions have been established for c-Myc and promyelocytic leukemia (PML) protein, respectively. Myc is known to inhibit differentiation of hematopoietic precursor cells, and here we report that PML promotes cell differentiation. We further demonstrate that PML and Myc form a complex in vivo. The interaction of the two proteins leads to the destabilization of Myc in a manner dependent on the really interesting new gene (RING) domain of PML. Although several PML isoforms are able to interact with Myc, the ability to destabilize Myc is specific for PML4. Importantly, the PML-induced destabilization resulted in a reduction of promoter-bound Myc on Myc-repressed genes. Thereby, PML induced the re-activation of Myc-repressed target genes including the tumor suppressive genes of the cell cycle inhibitors cdkn1a/p21 and cdkn2b/p15. Together, these results establish PML-mediated destabilization of Myc and the derepression of cell cycle inhibitor genes as an important regulatory mechanism that allows cell differentiation and prevents aberrant proliferation driven by uncontrolled Myc activity.     

Myc-driven murine prostate cancer shares molecular features with human prostate tumors

Increased Myc gene copy number is observed in human prostate cancer. To define Myc's functional role, we generated transgenic mice expressing human c-Myc in the mouse prostate. All mice developed murine prostatic intraepithelial neoplasia followed by invasive adenocarcinoma. Microarray-based expression profiling identified a Myc prostate cancer expression signature, which included the putative human tumor suppressor NXK3.1. Human prostate tumor databases revealed modules of human genes that varied in concert with the Myc prostate cancer signature. This module includes the Pim-1 kinase, a gene known to cooperate with Myc in tumorigenesis, and defines a subset of human, "Myc-like" human cancers. This approach illustrates how genomic technologies can be applied to mouse cancer models to guide evaluation of human tumor databases.