Catherine Denicourt, Ph.D.

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Cell Cycle Regulation, Ribosome Biogenesis, Cancer and Metastasis

核糖体生物发生项目
How cancers up-regulate their synthesis of ribosome to support growth and proliferation

The synthesis of ribosome is aberrantly increased in almost all cancers. The rate-limiting step in ribosome biogenesis is the production of the ribosomal RNA (rRNA), which is found dramatically unregulated in cancers. Strikingly, tumors are found to be much more sensitive than normal cells to the inhibition of rRNA production, indicating that pathways involved in the regulation of rRNA synthesis constitute a therapeutic vulnerability for cancers. Our goal is to identify novel means to block rRNA synthesis to limit the proliferation and survival of cancer cells. A critical barrier to developing affective inhibitor of rRNA synthesis is our poor understanding of the molecular mechanisms responsible for the aberrant regulation of rRNA production in cancers. Thus, a lot of our projects are focused on identifying novel pathways and key regulators of rRNA transcription in cancer cells. We recently uncovered that the transcriptional regulator and oncogene Pelp1 is part of an essential rRNA processing complex required for the production of the 28S rRNA. We are currently identifying the mechanisms by which Pelp1 regulates rRNA synthesis during breast cancer development.

证据表明,癌症也连续ce specialized ribosomes that selectively translate a proteome supporting cellular transformation and tumor development. One mechanism by which this alteration in ribosome function occurs in cancer is through aberrant changes in the methylation pattern of the rRNA. Because the rRNA constitutes the catalytic core of the ribosome, methylation of its residue directly affects translation accuracy and specificity towards certain types of mRNAs. Although several rRNA methyltransferases are found overexpressed in cancers, pathways regulating their function as well as how their activity shapes the cancer proteome are poorly understood. Our goal is to identify breast cancer-specific rRNA methylation patterns and determine how these changes influence ribosome function. We are particularly interested in identifying mRNAs preferentially translated by these cancer-specific ribosomes.

Cell Cycle Regulation Projects
The roles of p27Kip1 in the G1 to S-phase transition of the cell cycle

细胞周期是细胞用来忠实复制其DNA并在两个子细胞之间平均分离其重复的染色体的事件序列。细胞周期蛋白通过与细胞周期蛋白依赖性激酶（CDKS）结合并激活细胞周期。细胞周期蛋白-CDK复合物对特定靶标的磷酸化设置在运动不同的细胞过程中，这些过程及时驱动细胞周期。CDK受到CDK抑制剂的负调节，这些抑制剂与其物理缔合并抑制其活性以促进细胞周期停滞。细胞在细胞周期的G1期间致力于增殖。从静息G0阶段进入细胞周期的决定受到养分和有丝分裂剂等细胞外信号的总和。当细胞不再需要生长因子完成细胞分裂时，G1中发生承诺的点被称为限制点。一旦细胞通过了这一点，他们就会不可逆转地致力于完成分裂。这个复杂的分子检查点在许多级别上影响细胞周期设备，仍然鲜为人知。然而，众所周知，G1/S检查点的丧失是癌症开始的重要一步。 Our lab studies the signaling pathways that govern the G1 to S phase progression to better understand their deregulation during cancer development. We are particularly interested in the cyclin-CDK inhibitor p27Kip1, which was first identified as a negative regulator of G1 progression.

Based on tumor predisposition of p27Kip1 null mice, p27Kip is regarded as a nuclear tumor suppressor. However, human malignancies rarely select for deletion/inactivation of the p27Kip1 gene, a hallmark of tumor suppressor genes. Instead, p27Kip1 is often found either absent or relocalized to the cytoplasm in some aggressive metastatic cancers. We found that p27Kip1 is strongly present in the cytoplasm of human invasive and metastatic melanomas. Using in vivo models of metastasis, we demonstrated that cytoplasmic p27Kip1 dramatically increase the metastatic potential of melanoma.

实验室项目：

• 开发转基因小鼠模型以研究细胞质p27kip在乳腺癌中的作用。
• 确定p27KIP1在乳腺癌干细胞中的作用。
• 新型哺乳动物细胞周期蛋白的鉴定和表征。

出版物

出版信息

• Castle CD，Sardana R，Dandekar V，Borgianini V，Johnson AW和Denicourt C。(2013) Las1 interacts with Grc3 polynucleotide kinase and is required for ribosome synthesis in酿酒酵母。核酸研究beplay苹果手机能用吗。41：1135-1150。
• 城堡CD，Cassimere EK和Denicourt C.（2012）LAS1L与哺乳动物RIX1复合物相互作用以调节核糖体生物发生。摩尔。生物。细胞。23：716-728。
• Castle CD，Sardana R，Dandekar V，Borgianini V，Johnson AW和Denicourt C.（2012）LAS1与GRC3多核苷酸激酶相互作用，是核糖体合成所必需的酿酒酵母。核酸res。doi：10.1093/nar/gks1086。
• 城堡CD，Cassimere EK，Lee J和Denicourt C。(2010). Las1L is a nucleolar protein required for cell proliferation and ribosome biogenesis.摩尔细胞生物30, 4404-4414.
• Denicourt C，Saenz CC，Datnow B，Cui XC和Dowdy SF。（2007）。重新定位的P27KIP1肿瘤抑制剂在黑色素瘤中充当细胞质转移性癌。癌症。67：9238-9243。
• 拒绝C，Legault P，McNabb FA和Rassart E.（2007）。人和小鼠细胞周期蛋白D2剪接变体：转化活性和亚细胞定位。Oncogene27：1253-1262。
• Snyder EL, Saenz CC,Denicourt C，Meade BR，Cui XS，Kaplan IM和Dowdy SF。（2005）。通过可转导抗癌肽表达CXC趋化因子受体4的肿瘤细胞的靶向和杀伤增强。癌症。65：10646-10650。
• Denicourt C和Dowdy SF。（2004）。CIP/KIP蛋白：不仅仅是CDKS抑制剂。基因和开发。18:851-855.