Gene transcription and ubiquitin-mediated proteolysis are two processes that have seemingly nothing in common: transcription is the first step in the life of any protein and proteolysis the last. Despite the disparate nature of these processes, a growing body of evidence indicates that ubiquitin and the proteasome are intimately involved in gene control. Here, we discuss the deep mechanistic connections between transcription and the ubiquitin-proteasome system, and highlight how the intersection of these processes tightly controls expression of the genetic information.

Myc is an oncoprotein transcription factor that plays a prominent role in cancer. Like many transcription factors, Myc is an unstable protein that is destroyed by ubiquitin (Ub)-mediated proteolysis. Here, we report that the oncoprotein and Ub ligase Skp2 regulates Myc ubiquitylation and stability. Because of the growing number of Ub ligases that function as transcriptional coactivators, we speculated that Skp2 might also regulate Myc's transcriptional activity. Consistent with this model, we also show that Skp2 is a transcriptional coactivator for Myc, recognizing an essential element within the Myc activation domain and activating Myc target genes. These data suggest that Skp2 functions to connect Myc activity and destruction, and reveal an unexpected oncoprotein connection that may play an important role in controlling cell growth in normal and cancer cells.

The c-Myc oncoprotein promotes proliferation and apoptosis, such that mutations that disable apoptotic programmes often cooperate with MYC during tumorigenesis. Here we report that two common mutant MYC alleles derived from human Burkitt's lymphoma uncouple proliferation from apoptosis and, as a result, are more effective than wild-type MYC at promoting B cell lymphomagenesis in mice. Mutant MYC proteins retain their ability to stimulate proliferation and activate p53, but are defective at promoting apoptosis due to a failure to induce the BH3-only protein Bim (a member of the B cell lymphoma 2 (Bcl2) family) and effectively inhibit Bcl2. Disruption of apoptosis through enforced expression of Bcl2, or loss of either Bim or p53 function, enables wild-type MYC to produce lymphomas as efficiently as mutant MYC. These data show how parallel apoptotic pathways act together to suppress MYC-induced transformation, and how mutant MYC proteins, by selectively disabling a p53-independent pathway, enable tumour cells to evade p53 action during lymphomagenesis.Human tumours frequently show deregulated expression of the c-Myc proto-oncogene [1][2][3] . In Burkitt's lymphoma, this deregulation occurs through reciprocal translocations that juxtapose c-Myc with an immunoglobulin (Ig) promoter, leading to gross overexpression of c-Myc messenger RNA in the B cell lineage 4,5 . In addition, point mutations are often found in the translocated MYC alleles, clustering in a conserved region known asMYC box I (refs 6-8). Although some mutations can increase MYC stability and transforming activity in vitro, their impact on the pathogenesis of Burkitt's lymphoma is unclear [9][10][11][12][13][14][15][16] . In fact, Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. Correspondence and requests for materials should be addressed to S.W.L. (lowe@cshl.org). * These authors contributed equally to this work.Supplementary Information is linked to the online version of the paper at www.nature.com/nature.The authors declare no competing financial interests. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript translocated c-Myc genes are subject to hypermutation in vivo that can also alter non-coding sequences, raising the possibility that these mutations are a consequence and not a cause of tumour development 17,18 .To examine the effects of MYC mutation on lymphoma development in vivo, we used a system for rapidly generating tissue-specific transgenic mice (see Supplementary Fig. 1). Two mutant MYC alleles commonly observed in Burkitt's lymphoma (P57S and T58A) 13 were cloned into a murine stem cell virus (MSCV)-based vector that co-expresses green fluorescent protein (GFP). Haematopoietic stem cells (HSCs) derived from normal fetal livers were transduced with retroviruses expressing either wild-type or mutant MYC, and the genetically modified stem cells were then used to reconstitute the haematopoietic system of lethally irradiated recipient animals. This adop...

The human proto-oncogene c-myc encodes a highly unstable transcription factor that promotes cell proliferation. Although the extreme instability of Myc plays an important role in preventing its accumulation in normal cells, little is known about how Myc is targeted for rapid destruction. Here, we have investigated mechanisms regulating the stability of Myc. We show that Myc is destroyed by ubiquitin-mediated proteolysis, and define two elements in Myc that oppositely regulate its stability: a transcriptional activation domain that promotes Myc destruction, and a region required for association with the POZ domain protein Miz-1 that stabilizes Myc. We also show that Myc is stabilized by cancer-associated and transforming mutations within its transcriptional activation domain. Our data reveal a complex network of interactions regulating Myc destruction, and imply that enhanced protein stability contributes to oncogenic transformation by mutant Myc proteins.

SUMMARY MYC is an oncoprotein transcription factor that is overexpressed in the majority of malignancies. The oncogenic potential of MYC stems from its ability to bind regulatory sequences in thousands of target genes, which depends on interaction of MYC with its obligate partner, MAX. Here, we show that broad association of MYC with chromatin also depends on interaction with the WD40-repeat protein WDR5. MYC binds WDR5 via an evolutionarily conserved “MYC box IIIb” motif that engages a shallow, hydrophobic, cleft on the surface of WDR5. Structure-guided mutations in MYC that disrupt interaction with WDR5 attenuate binding of MYC to ~80% of its chromosomal locations and disable its ability to promote induced pluripotent stem cell formation and drive tumorigenesis. Our data reveal WDR5 as a key determinant for MYC recruitment to chromatin and uncover a tractable target for the discovery of anti-cancer therapies against MYC-driven tumors.