No abstract

This year the most prestigious prize in medical sciences, the Lasker Award, has been presented to the three scientists who discovered the ubiquitin pathway: Aaron Ciechanover, Avram Hershko, and Alexander Varshavsky [Nature Med. 6 (2000) 1073^1081]. During a time when the scientific community was focused on understanding how proteins were synthesized, they intently pursued the novel idea that cells were programmed to selectively destroy proteins. Their work led to the identification of an elaborate system of protein degradation targeting a myriad of cellular substrates. A small protein called ubiquitin is at the center of this process. Although the ubiquitin pathway was first described in the early 1980s, it has only more recently advanced to the forefront of basic research as a significant regulatory network within the cell. The field continues to grow as new ubiquitination enzymes and novel functions of this system are identified. Scientists are focused on elucidating the mechanisms by which cells deploy the ubiquitin pathway to control levels of selected proteins, such as cell cycle regulatory proteins, transcription factors and signaling molecules. Accelerated or decelerated rates of degradation of particular substrates participate in the genesis of many human diseases. Thus, understanding the mechanisms that confer specificity to the ubiquitin system will allow the development of novel therapeutic approaches to target aberrations in this pathway underlying tumorigenesis and other human pathologies. ß

The ubiquitin pathway is involved in the proteolytic turnover of many short-lived cellular regulatory proteins. Since selective degradation of substrates of this system requires the covalent attachment of a polyubiquitin chain to the substrates, degradation could be counteracted by de-ubiquitinating enzymes (or isopeptidases) which selectively remove the polyubiquitin chain. Unp is a human isopeptidase with still poorly understood biological functions. Here, we show that cellular Unp speci®cally interacts with the retinoblastoma gene product (pRb). Oncogene (2001) 20, 5538 ± 5542.

No abstract

The MYC oncogene induces a multitude of human malignancies and has been well characterized as a critical driver of select lymphoma subtypes. In MYC-amplified tumor progression, there is a robust dependence on MYC activity; however, strategies developed to modulate MYC function in cancer have yielded little success. Patients harboring these MYC-driven tumors would benefit from a directed therapy that circumvents explicit molecular targeting of MYC expression. Our preliminary data from an unbiased expression-profiling screen identified CD30 as a primary downstream target of the MYC oncoprotein. CD30 is a member of the tumor necrosis factor superfamily and resides on the extracellular membrane; it is highly expressed in many lymphomas while acutely restricted in normal cells. Within the last few decades, CD30 has emerged as a diagnostic marker and therapeutic target of many lymphoproliferative disorders and diseases. The biological function of CD30 is pleiotropic: CD30 stimulation is reportedly linked to cell cycle arrest, apoptosis, and proliferation through activation of the pro-survival transcription factor, NF-kB. However, the underlying mechanisms that regulate CD30 expression remain unclear. CD30-driven oncogenic pathways phenocopy those initiated by MYC, suggesting CD30's potential status as an effector of MYC-driven tumorigenic events. Here we report that CD30 is regulated at the transcriptional level by MYC. Through a genetic and biochemical approach, we define CD30 induction in a MYC-dependent manner across a variety of human cell lines of both lymphomagenic and non-lymphomagenic origin. Furthermore, in a murine lymphoma model where tumor formation is driven by a conditional allele of MYC, CD30 transcript levels are tightly correlated with MYC activity. Ultimately, CD30 induction offers a novel therapeutic avenue by which to target MYC-driven oncogenesis and has the potential to reshape detection and treatment of MYC-regulated cancer. Citation Format: Victoria Gennaro, Xiao-yong Zhang, Lauren DeSalle, Duonan Yu, Andrei Thomas-Tikhonenko, Steven McMahon. CD30: A therapeutic target of MYC-driven cancer. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A40.

Pathological activation of the transcription factor Myc induces a multitude of human malignancies. In Myc-driven tumor progression, there is a robust dependence on Myc activity; however, strategies developed to explicitly modulate Myc function in cancer have yielded little clinical success. Patients harboring Myc-dependent tumors would benefit from a therapy that circumvents molecular targeting of Myc expression and instead directs against a distinct downstream effector. Our preliminary data from an unbiased expression-profiling screen identify CD30 as a primary target of the Myc oncoprotein. CD30 is a member of the tumor necrosis factor superfamily and resides on the extracellular membrane; it is highly expressed in several lymphomas while acutely restricted in normal cells. Within the last few decades, CD30 has emerged as a diagnostic marker and therapeutic target of many lymphoproliferative diseases. However, the underlying mechanisms that regulate CD30 expression remain unclear. We report that CD30 is regulated at the transcriptional level by Myc. Through a genetic and biochemical approach, we define CD30 induction in a MYC-dependent manner across a variety of human cell lines of both lymphomagenic and non-lymphomagenic origin. Furthermore, deliberate modulation of Myc-activity demonstrates a positive correlation with CD30 surface protein expression in multiple malignancy models. With CD30 induction as a potential mechanism by which to identify and target Myc-driven oncogenesis, we can reshape detection and treatment of Myc-regulated cancer. Citation Format: Victoria Gennaro, Xiao-yong Zhang, Lauren DeSalle, Duonan Yu, Andrei Thomas-Tikhonenko, Christopher Vakoc, Steven B. McMahon. Identification of CD30/TNFRSF8 as a primary target of the Myc oncoprotein and potential biomarker of Myc-driven cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4553.