Polypoid cell cycle regulation and genome instability

息肉样细胞周期调控和基因组不稳定性

• 批准号: 10410419
• 负责人: BRIAN R CALVI
• 金额: $ 31.85万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-12 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410419
• 关键词: Address; Affect; Aneuploid Cells; Aneuploidy; Apoptosis; Apoptotic; Back; Binding; Biochemical Genetics; Biological; Biological Process; Blood; CDC2 gene; Cell Cycle; Cell Cycle Regulation; Cell Death; Cell Size; Cell Survival; Cell division; Cells; Cellular Stress; Chromatin; Chromosomal Instability; Competence; Cycas; DNA; DNA Damage; Data; Development; Disease; Drosophila genus; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Transcription; Genomic Instability; Genotoxic Stress; Growth; Health; Heart; Human; Knowledge; Lead; Link; Liver; MYB gene; Malignant Neoplasms; Maps; Mediating; Methods; Mitosis; Mitotic; Modification; Molecular; Mosaicism; Mus; Mutation; Natural regeneration; Nature; Neoplasm Metastasis; Neoplasms; Normal tissue morphology; Oncogenic; Outcome; Pathway interactions; Phosphorylation; Phosphorylation Site; Physiologic pulse; Ploidies; Polyploid Cells; Polyploidy; Property; Regenerative Medicine; Regulation; Repression; Resistance; Skin; Stress; TP53 gene; Testing; Tissues; Transcription Coactivator; Transcription Repressor; Transcriptional Activation; Variant; base; biological adaptation to stress; cancer cell; cancer therapy; cell type; chromatin modification; daughter cell; defined contribution; design; experimental study; fly; genetic approach; in vivo; novel therapeutics; programs; promoter; radiation response; response; tool; transcription factor; tumor; tumor progression; tumorigenesis; wound healing

SUMMARY Cell division and stress response differ among tissues and are perturbed in disease. This proposal focuses on a variation called the endocycle, during which cells periodically replicate their DNA without dividing, resulting in an increase in cell size and cellular DNA content (polyploidy). This alternative growth program occurs widely in nature, including many tissues in humans (e.g. liver, heart, blood, skin). Emerging evidence indicates that cells also switch to endocycles during wound healing, regeneration, and cancer. Despite their importance, much remains unknown about how endocycles are regulated and how they contribute to tissue growth and disease. The objectives of this proposal are to define the molecular and cellular mechanisms that regulate endocycles, their modified response to DNA damage, and their contribution to genome instability and cancer. Our previous studies showed that endocycling cells in the fruit fly do not undergo programmed cell death (apoptosis) in response to radiation or other treatments that damage DNA, a property that others have shown is shared by endocycling cells in mice. The repression of cell death acts through chromatin silencing of target genes of the p53 tumor suppressor. Our previous studies also showed that both fly and human cells can be induced to switch to endocycles, and then can switch back to mitotic divisions that are extremely error prone, resulting in daughter cells with abnormal DNA content (aneuploidy). It is known that human cancer cells are frequently aneuploid and that tumors contain giant polyploid cells. Together, these observations lead to the hypothesis that a transient switch to endocycles leads to cancer cell survival with a return to mitosis causing mutations that promote cancer progression. This proposal seeks to understand the molecular mechanisms that regulate endocycles, repress apoptosis, and contribute to tumor formation and metastasis. We will use the powerful tools in the fruit fly to achieve three specific aims: 1) To determine how the repression of apoptosis is linked to the endocycle program, 2) To define the mechanism by which CycA / CDK activates the Myb-MuvB to regulate alternative cell cycle programs, 3) To determine the contribution of transient endocycles to oncogenic growth and metastasis. The outcomes of this proposal will fill a major knowledge gap in understanding the regulation of the variant endocycle growth program and its contributions to development and cancer, ultimately leading to better regenerative medicine and cancer therapies.

总结 细胞分裂和应激反应在组织中不同，在疾病中受到干扰。该提案的重点是 一种称为内循环的变异，在此期间，细胞周期性地复制它们的DNA而不分裂， 细胞大小和细胞DNA含量增加（多倍性）。这种替代增长方案广泛存在于 自然界，包括人类的许多组织（如肝脏、心脏、血液、皮肤）。新的证据表明， 在伤口愈合、再生和癌症期间也转变为内循环。尽管其重要性， 对于内循环是如何调节的以及它们如何促进组织生长和疾病仍然是未知的。 本提案的目的是确定调节内循环的分子和细胞机制， 它们对DNA损伤的修饰反应，以及它们对基因组不稳定性和癌症的贡献。我们以前的 研究表明，果蝇中的内循环细胞不会发生程序性细胞死亡（凋亡）， 对辐射或其他损伤DNA的治疗的反应，其他人已经表明， 小鼠的内循环细胞。细胞死亡的抑制作用是通过染色质沉默的靶基因， p53肿瘤抑制因子。我们以前的研究也表明，苍蝇和人类细胞都可以被诱导， 转变为内循环，然后可以转变回极容易出错的有丝分裂， DNA含量异常的子细胞（非整倍体）。众所周知，人类癌细胞经常 非整倍体和肿瘤含有巨大的多倍体细胞。这些观察结果共同导致了一个假设 内循环的瞬时转换导致癌细胞存活并返回有丝分裂， 促进癌症发展的基因这项提案旨在了解调节细胞凋亡的分子机制。 内循环，抑制细胞凋亡，并有助于肿瘤形成和转移。我们会利用强大的力量 在果蝇中的工具，以实现三个具体的目标：1）确定细胞凋亡的抑制是如何联系到 2）明确CycA/CDK激活Myb-MuvB调控Myb-MuvB的机制 3）确定瞬时内循环对致癌生长的贡献 和转移。该提案的结果将填补理解该法规的主要知识空白 变异内循环生长程序及其对发育和癌症的贡献，最终导致 更好的再生医学和癌症疗法。

项目成果

Different cell cycle modifications repress apoptosis at different steps independent of developmental signaling in Drosophila.

• DOI: 10.1091/mbc.e16-03-0139
• 发表时间: 2016-06-15
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Qi S;Calvi BR
• 通讯作者: Calvi BR

Drosophila p53 isoforms have overlapping and distinct functions in germline genome integrity and oocyte quality control.

• DOI: 10.7554/elife.61389
• 发表时间: 2022-01-13
• 期刊: eLife
• 影响因子: 7.7
• 作者: Chakravarti A;Thirimanne HN;Brown S;Calvi BR
• 通讯作者: Calvi BR

Transient endoreplication down-regulates the kinesin-14 HSET and contributes to genomic instability.

• DOI: 10.1091/mbc.e16-03-0159
• 发表时间: 2016-10-01
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Chen S;Stout JR;Dharmaiah S;Yde S;Calvi BR;Walczak CE
• 通讯作者: Walczak CE

A Cyclin A-Myb-MuvB-Aurora B network regulates the choice between mitotic cycles and polyploid endoreplication cycles.

Cyclin A-Myb-MuvB-Aurora B 网络调节有丝分裂周期和多倍体内复制周期之间的选择。

• DOI: 10.1371/journal.pgen.1008253
• 发表时间: 2019
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Rotelli,MichaelD;Policastro,RobertA;Bolling,AnnaM;Killion,AndrewW;Weinberg,AbrahamJ;Dixon,MichaelJ;Zentner,GabrielE;Walczak,ClaireE;Lilly,MaryA;Calvi,BrianR
• 通讯作者: Calvi,BrianR