Project 3: D. Spector Long Nuclear-Retained Non-Coding RNAs and Cancer Hannon, Gregory J PROJECT SUMMARY (See instructions): Long nuclear retained non-coding RNAs (IncRNAs) represent a large and relafively unmined class of RNAs that are likely to play critical roles in gene regulafion and disease etiology. A major challenge is to understand the molecular functions of specific IncRNAs both at the cellular level and within the context of an organism. The long-term goal of this project is to identify and characterize IncRNAs that play a critical role in mammary gland development and the inifiation and progression of breast cancer. Here, a series of Aims are presented to dissect out the role of Malati, an abundant IncRNA localized to nuclear speckles and focally amplified in a significant number of metastatic breast cancers. Studies are proposed to develop innovative loss-of-function and gain-of-function mouse models combined with cell biological approaches to assess the function of Malati in normal development and in breast cancer initiation and metastasis. The impact of alterations in the level of Malati on tissue organization will be examined, and its effect on alternative splicing in a tissue-specific manner will be pursued by next-generation RNA-sequencing analyses. Complementary cell biological studies will delve into the role that Malati plays in nuclear organization and its impact on the dynamics of pre-mRNA splicing factors enriched in nuclear speckles. The Malati RNP will be purified using an RNA-tagging strategy and its proteome will be characterized in order to idenfify proteins responsible for its nuclear retention and to provide additional insight into its function. In the final Aim a series of newly identified IncRNAs, that are misregulated in breast cancer, will be prioritized and several will be selected for functional analyses, to identify genes and pathways that they target, and to elucidate the mechanisms by which they contribute to breast cancer tumorigenesis. Together, the proposed studies will provide important insights into the role of several IncRNAs in normal development and cancer and will lead to new opportunities for the identification and characterizafion of a new and excifing class of potential therapeutic targets.
This study will examine the role of several long nuclear retained non-coding RNAs in mouse development and in the initiation and progression of breast cancer. LncRNAs represent a relatively new and unexplored class of potential diagnostic and therapeutic targets with roles in regulating aspects of gene expression. Then sights gained from the proposed studies will add significantly to our understanding of breast cancer and potential treatment options.
|Chakraborty, A A; Scuoppo, C; Dey, S et al. (2015) A common functional consequence of tumor-derived mutations within c-MYC. Oncogene 34:2406-9|
|Mazurek, Anthony; Park, Youngkyu; Miething, Cornelius et al. (2014) Acquired dependence of acute myeloid leukemia on the DEAD-box RNA helicase DDX5. Cell Rep 7:1887-99|
|Huang, Chun-Hao; Lujambio, Amaia; Zuber, Johannes et al. (2014) CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev 28:1800-14|
|Saborowski, Michael; Saborowski, Anna; Morris 4th, John P et al. (2014) A modular and flexible ESC-based mouse model of pancreatic cancer. Genes Dev 28:85-97|
|Fellmann, Christof; Lowe, Scott W (2014) Stable RNA interference rules for silencing. Nat Cell Biol 16:10-8|
|Jensen, Mads A; Wilkinson, John E; Krainer, Adrian R (2014) Splicing factor SRSF6 promotes hyperplasia of sensitized skin. Nat Struct Mol Biol 21:189-97|
|Weissmueller, Susann; Manchado, Eusebio; Saborowski, Michael et al. (2014) Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor ? signaling. Cell 157:382-94|
|Bolden, Jessica E; Tasdemir, Nilgun; Dow, Lukas E et al. (2014) Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition. Cell Rep 8:1919-29|
|Chen, Chong; Liu, Yu; Rappaport, Amy R et al. (2014) MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell 25:652-65|
|Das, Shipra; Krainer, Adrian R (2014) Emerging functions of SRSF1, splicing factor and oncoprotein, in RNA metabolism and cancer. Mol Cancer Res 12:1195-204|
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