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Binational  Science  Foundation  (BSF)  <br/><br/>Final  Scientifc  Report  October  2012 <br/><br/>Grant number: 2007307 <br/>PI’s: Elazar Zelzer <br/><br/>Randall S. Johnson <br/><br/> <br/><br/>  <br/><br/>HIF-1α is a central regulator of collagen hydroxylation and secretion <br/><br/>under hypoxia* <br/><br/> <br/>Collagen production is fundamental for the ontogeny as well as the phylogeny of all <br/>multicellular organisms. It depends on hydroxylation of proline residues, a reaction that <br/>utilizes molecular oxygen as a substrate. Nevertheless, during embryogenesis various tissues <br/>develop under low oxygen levels, implying that a specific mechanism had to evolve to <br/>resolve this seeming paradox. <br/>Here, we identify the transcription factor hypoxia-inducible factor 1 alpha (HIF-1α) as a <br/>central regulator of collagen hydroxylation and secretion by hypoxic cells. Using the growth <br/>plate of developing bones as a model system, we show that Hif-1α loss-of-function in <br/>chondrocytes arrests secretion of extracellular matrix proteins, including collagen type II. <br/>Reduced collagen hydroxylation and endoplasmic reticulum (ER) stress observed in Hif-1α-<br/>depleted cells suggest that HIF-1α controls collagen hydroxylation and folding. As a <br/>molecular mechanism, we demonstrate in vivo that HIF-1α drives transcription of the <br/>hydroxylation catalyst collagen prolyl 4-hydroxylase (cP4H). Concurrently, HIF-1α <br/>maintains cellular levels of the substrate oxygen by controlling expression of pyruvate <br/>dehydrogenase kinase 1 (PDK1), an inhibitor of the tricarboxylic acid (TCA) cycle. Through <br/>this two-armed mechanism, HIF-1α activity allows chondrocytes to function as professional <br/>secretory cells under hypoxic conditions in the growth plate. Since hypoxic conditions also <br/>occur during pathological conditions such as cancer, our findings may promote the <br/>understanding not only of embryogenesis, but of pathological processes as well. <br/> <br/>* This study has been accepted for publication in the peer-reviewed journal Development <br/>(Bentovim et al., 2012).

PROJECT SUMMARY Founded in 1977 by John Mendelsohn, the Cancer Center at University of California San Diego (UCSD) has been continuously funded by the NCI Cancer Center Support Grant (CCSG) since 1978 and has held Comprehensive status since 2001. As the only NCI-designated Comprehensive Cancer Center in San Diego County, the mission of Moores Cancer Center (MCC) is to reduce the impact of cancer in the region and beyond by fostering scientific discovery, research training, and interdisciplinary care. Our goal is to create, translate, and deliver high-impact discoveries and innovations in cancer prevention and care through a deep understanding of the needs of the catchment area, and prepare the next generation of cancer researchers. Accordingly, MCC’s aims are to: 1) Elucidate the biology of cancer and catalyze trans-disciplinary team science across the science spectrum

2) Develop and test innovative preventive, diagnostic, and therapeutic approaches

3) Conduct cancer prevention and control research to reduce cancer disparities in vulnerable populations

4) Provide underrepresented minorities with access to cutting edge multi-disciplinary care

5) Provide training and education across the trainee continuum

and 6) Develop and implement community-based cancer education and outreach programs. To this end, MCC brings together 232 members from 5 UCSD Schools (Medicine, Engineering, Pharmacy and Pharmaceutical Sciences, Physical Sciences and Biological Sciences) and 2 consortium partners (one existing: San Diego State University, and one new: La Jolla Institute). Furthermore, MCC integrates the resources of UCSD Health Sciences and its affiliated hospitals in the UCSD Health System for a unified approach to cancer research and clinical care. MCC fulfills its mission through the activities of its 5 Research Programs (Cancer Biology and Signaling, Structural and Functional Genomics, Solid Tumor Therapeutics, Hematological Malignancies, and Cancer Control) that are supported by 7 Shared Resources (Flow Cytometry, Microscopy, Transgenic Mouse, Biostatistics, Genomics and Computational Biology, Biorepository and Tissue Technology, and Biobehavioral), and infrastructure provided by Community Outreach, Training and Education, Clinical Protocol and Data Management, and Protocol Review and Monitoring. Under the leadership of Dr. Scott Lippman, Center Director and Associate Vice- Chancellor for Cancer Research and Care, MCC has seen tremendous growth. During the project period, MCC members authored 3931 cancer-relevant research articles, and in 2017 were supported by $128.2 million (DC) in annual cancer-relevant peer-reviewed funding (8% increase)

and the total annualized cancer-relevant research base was $148.5M, an increase of 11% from the previous project period by lateral comparison. Collaborative peer-reviewed grant funding also increased from annual total costs of $65.9M in 2013 to $69.9M in 2017 (6% increase). Importantly, 33 of MCC’s scientific discoveries were translated to the clinic through 41 investigator-initiated clinical trials, a 14-fold increase from the previous project period.