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16.5E: Cancer and Translational Control - Biology

16.5E: Cancer and Translational Control - Biology


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Cancer can arise from translational or post-translational modifications of proteins.

Learning Objectives

  • Determine how translational or post-translational modifications can lead to cancer

Key Points

  • Protein modifications from the increased translation of a protein to changes in protein phosphorylation to alternative splice variants of a protein are found in cancer cells.
  • The expression of the wrong protein dramatically alters cell function and contributes to the progression of cancer.
  • Gene regulation and gene function provide scientists with the opportunity to design medicines and therapies that specifically target diseased cells or exploit the overexpression of specific proteins as cancer treatment.

Key Terms

  • targeted therapy: a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules rather than by interfering with rapidly dividing cells
  • cancer: a disease in which the cells of a tissue undergo uncontrolled (and often rapid) proliferation
  • post-translational modification: the chemical modification of a protein after its translation; one of the later steps in protein biosynthesis, and thus gene expression, for many proteins

Cancer and Translational/Post-translational Control

There are many examples of translational or post-translational modifications of proteins that arise in cancer. Modifications are found in cancer cells from the increased translation of a protein to changes in protein phosphorylation to alternative splice variants of a protein. An example of how the expression of an alternative form of a protein can have dramatically different outcomes is seen in colon cancer cells. The c-Flip protein, a protein involved in mediating the cell death pathway, comes in two forms: long (c-FLIPL) and short (c-FLIPS). Both forms appear to be involved in initiating controlled cell death mechanisms in normal cells. However, in colon cancer cells, expression of the long form results in increased cell growth instead of cell death. Clearly, the expression of the wrong protein dramatically alters cell function and contributes to the development of cancer.

New Drugs to Combat Cancer: Targeted Therapy

Scientists are using what is known about the regulation of gene expression in disease states, including cancer, to develop new ways to treat and prevent disease development. Many scientists are designing drugs on the basis of the gene expression patterns within individual tumors. This idea, that therapy and medicines can be tailored to an individual, has given rise to the field of personalized medicine. With an increased understanding of gene regulation and gene function, medicines can be designed to specifically target diseased cells without harming healthy cells. Some new medicines, called targeted therapies, have exploited the overexpression of a specific protein or the mutation of a gene to develop a new medication to treat disease. One such example is the use of anti-EGF receptor medications to treat the subset of breast cancer tumors that have very high levels of the EGF protein. Undoubtedly, more targeted therapies will be developed as scientists learn more about how gene expression changes can cause cancer.


Cancer can be described as a disease of altered gene expression. There are many proteins that are turned on or off (gene activation or gene silencing) that dramatically alter the overall activity of the cell. A gene that is not normally expressed in that cell can be switched on and expressed at high levels. This can be the result of gene mutation or changes in any level of gene regulation (epigenetic, transcription, post-transcription, translation, or post-translation).

Changes in epigenetic regulation, transcription, RNA stability, protein translation, and post-translational control can be detected in cancer. While these changes don’t occur simultaneously in one cancer, changes at each of these levels can be detected when observing cancer at different sites in different individuals. Therefore, changes in histone acetylation (epigenetic modification that leads to gene silencing), activation of transcription factors by phosphorylation, increased RNA stability, increased translational control, and protein modification can all be detected at some point in various cancer cells. Scientists are working to understand the common changes that give rise to certain types of cancer or how a modification might be exploited to destroy a tumor cell.


Colin C. C. Wu, Ph.D.

We are exploring the role of the ribosome in stress response signaling pathways and translational regulation in mammalian systems. To this end, we have developed an improved ribosome footprint profiling methodology that allows us to monitor both the positions and the in vivo functional states of individual ribosomes. Most projects in the laboratory incorporate high-throughput genome-wide approaches, computational tools, and biochemical approaches to define the molecular mechanisms of these pathways in vivo. Our long-term goal aims to congregate actionable insights that can be used to guide the prevention and treatment of human diseases.

1) translational control, 2) ribosome, 3) RNA quality control, 4) RNA biology, 5) protein synthesis

Contact Info

Our laboratory is broadly interested in translational regulation during cellular stress, especially by the ribosome, ribosome-associated factors, and RNA binding proteins. We employ an integrated approach, combing mass spectrometry, CRISPR screens, high-throughput chemical probing, ribosome profiling, biochemical techniques, and computational tools to identify and characterize novel factors involved in stress sensing and fine-tuning the translational output.

Protein synthesis is essential in all cells. As such, a continuous flow of ribosomes along mRNAs needs to be maintained to support a healthy proteome. Ribosome stalling occurs under a variety of cellular stress conditions, including nutrient deprivation, hypoxia, and oxidative stress. To gain higher resolution into ribosome dynamics in vivo, we have developed an improved ribosome footprint profiling methodology that reveals not only the positions but also the functional states of individual ribosomes transcriptome-wide (Wu et al., Mol Cell 2019). If a stalled ribosome cannot be resolved before a trailing ribosome catches up, ribosome collisions occur. We recently discovered that colliding ribosomes serve as a platform that recruits collision-sensing factors and triggers two inter-related but distinct signaling pathways– the ribotoxic stress response and the integrated stress response– to regulate cell fate decisions (Wu et al., Cell 2020). We are now investigating the molecular mechanisms of this process and its potential implications in normal cell physiology during development and in disease-related settings such as cancer. Additionally, we’re also pursuing how local translation is coupled to RNA decay and cellular stress responses.


MD Anderson’s TRACTION platform

Creating a cancer drug typically takes years of research and testing. Cancer patients deserve better.

The TRACTION team deploys a comprehensive approach that includes disruptive technologies, cutting-edge disease modeling and enhanced data analytics to accelerate the pace of drug development and inform clinical translation. TRACTION unites industry-seasoned professionals with highly successful academic scientists forming cross-functional teams all working toward a singular goal – bringing our patients new, highly effective options. These teams are organized into three groups:

  • Discovery & Innovation: Employing advanced technology platforms and data analytics to evaluate new therapeutic concepts and opportunities that feed our drug discovery pipeline
  • Target Biology: Executing fundamental mechanistic studies on therapeutic targets to gain a deep understanding of underlying biology to guide development from concept to clinic
  • Translational Biology: Supporting drug development through state-of-the-art disease modeling, in vivo pharmacology and biomarker development capabilities

TRACTION functions as a translational-research hub at MD Anderson, promoting relationships across the institution to support highly innovative science aimed at addressing unmet clinical needs. TRACTION also engages with biopharmaceutical companies to build meaningful collaborations that align with institutional strengths and have the potential to bring impactful new therapies to MD Anderson patients.

Through this multidisciplinary approach, TRACTION fosters team science that spans basic, translational and clinical science disciplines, where expertise across MD Anderson is leveraged to drive innovation around programs with the best chance of catalyzing transformative advances.


Cancer Prevention and Control Program

The Cancer Prevention and Control (CPC) Program is the nexus for population sciences-focused research at Georgetown Lombardi. Its mission is to conduct innovative and impactful population sciences research across the translational continuum, from discovery to intervention to policy, to help alleviate the burden of cancer. A unique aspect of the CPC Program is its capacity to rapidly translate findings through the phases of this continuum within and across each of the Program’s scientific aims.

CPC appoints both full and associate members who address the cancer prevention-control needs of our catchment area through research focused on cancer risk factors and biomarkers, primary and secondary cancer prevention, and outcomes of cancer treatment and survivorship. Research in the catchment area is facilitated through community-based research sites, including the Capital Breast Care Center and the community-based Office of Minority Health and Health Disparities located in Southeast Washington, DC. CPC is also leading the development of the cancer center’s newly established Office for Global Health.

CPC Program members focus on three specific aims:

  • Aim 1: Cancer risk factors and biomarkers. We investigate genomic, biologic and other risks associated with cancer occurrence and early detection.
  • Aim 2: Primary and secondary cancer prevention. We develop and implement cancer prevention interventions and cancer screening to inform practices and policies that reduce cancer burdens.
  • Aim 3: Outcomes of cancer treatment and survivorship. We conduct clinical, translational and policy-relevant research on ways to treat cancer and promote improved survivorship.

In addition, cross-cutting themes of genetic/genomic underpinnings of cancer risk and response (in collaboration with the Fisher Center) and cancer burdens and disparities are integrated within each of the aims.

The CPC Program is also home to an FDA-funded center for tobacco research, is an active contributor to many cancer center-wide initiatives, including cancer survivorship, and provides leadership to MedStar Georgetown University Hospital’s Smoking Treatment and Recovery (STAR) and Cancer Survivorship programs. Our educational efforts take place across Georgetown University, including the Master’s in Epidemiology and Tumor Biology graduate training programs. Additionally, the program organizes fellowship training in cancer control and prevention science.

Promoting Collaboration

To help support programmatic science in all aspects of cancer control and prevention, CPC offers members several mechanisms that promote collaboration within and across the cancer center. This includes Idea Lab for brainstorming about early stage research concepts, Research Strategy Sessions for work-in-progress on ongoing studies and planned future directions, and Mock Study Section for peer review of extramural grant/contract applications prior to agency submission. Please contact the program’s leadership if interested in a hosted meeting. The program’s leadership is also instrumental in convening research affinity groups around focal and emerging areas of cancer population sciences, including cancer care delivery research, translational genomics, and in studying the burdens of cancer among older adults and long-term cancer survivors.


UORF-mediated translational control: recently elucidated mechanisms and implications in cancer

Protein synthesis is tightly regulated, and its dysregulation can contribute to the pathology of various diseases, including cancer. Increased or selective translation of mRNAs can promote cancer cell proliferation, metastasis and tumor expansion. Translational control is one of the most important means for cells to quickly adapt to environmental stresses. Adaptive translation involves various alternative mechanisms of translation initiation. Upstream open reading frames (uORFs) serve as a major regulator of stress-responsive translational control. Since recent advances in omics technologies including ribo-seq have expanded our knowledge of translation, we discuss emerging mechanisms for uORF-mediated translation regulation and its impact on cancer cell biology. A better understanding of dysregulated translational control of uORFs in cancer would facilitate the development of new strategies for cancer therapy.

AMPKAMP-activated protein kinase
C/EBPβCCAAT/enhancer binding protein β
CUGBP1CUG repeat RNA binding protein 1
DDIT3DNA damage inducible transcript 3
eEF2Keukaryotic elongation factor 2 kinase
EPHB1EPH receptor B1
HIF-1αhypoxia-inducible factor 1α
GADD3growth arrest and DNA damage-inducible protein
GCN2general control nonderepressible 2
HRIheme-regulated eIF2α kinase
LAPliver-enriched transcriptional activator protein
LIPliver-enriched transcriptional inhibitory protein
MAPKmitogen-activated protein kinase
MEHMOMental retardation, epileptic seizures, hypogenitalism, microcephaly and obesity
MNKMAPK-interacting kinases
mTORC1/2mammalian target of rapamycin complex 1/2
ODC1ornithine decarboxylase 1
PERKprotein kinase R-like endoplasmic reticulum kinase
PI3Kphosphoinositide 3-kinase
PKRRNA-dependent protein kinase PKR
PTP4AProtein tyrosine phosphatase Type IV A
SBDSThe Shwachman-Bodian-Diamond syndrome protein
VEGFAvascular endothelial growth factor A
YTHYT521-B homology

Acknowledgments

This work was supported by Institute of Biomedical Sciences, Academia Sinica, Taiwan, grant IBMS-CRC107-P03.


SELECTIVE ONCOGENIC ADVANTAGES OF DEREGULATED TRANSLATION

Proliferation and Apoptosis

A large body of research has shown translational regulation of antiapoptotic factors, cyclins, and cyclin-dependent kinases (Sonenberg 1994 Silvera et al. 2010 Ruggero 2013 Teng et al. 2013 de la Parra et al. 2017). Although the role of translation in cell proliferation and survival has historically been the focus of much of the research in this field, other hallmarks of cancer are also regulated at the level of translation, as delineated below (Fig. 2).

Angiogenesis

Tumor angiogenesis is an ongoing process of continuous remodeling to accommodate tumor growth and is promoted by a variety of translational mechanisms. The mRNAs encoding two major regulators of angiogenesis, VEGFA and HIF1α, are translated via a variety of mechanisms that ensure cancer cells’ ability to adapt to hypoxia. Thus, the translation of VEGFA and HIF1α mRNAs can be promoted by both cap-dependent and cap-independent mechanisms, via the use of IRESs, uORFs, and possibly other noncanonical regulatory elements (Lang et al. 2002 Braunstein et al. 2007 Bastide et al. 2008 Arcondeguy et al. 2013). Although their translation is associated with increased eIF4E expression in human tumors (Nathan et al. 1997 Scott et al. 1998 Dodd et al. 2015), the complex translational regulation of VEGFA and HIF1α mRNAs allows for their translation to be maintained even in profound hypoxia and nutrient deprivation. Interestingly, HIF1α binds to the EIF4E promoter to promote its transcription, suggesting the possibility that the response to hypoxia could switch from an initial cap-independent mechanism to a cap-dependent one (Yi et al. 2013).

Stress Responses

In addition to hypoxia, cancer cells must modulate translation in the face of a variety of other stresses (Young and Wek 2016 Robichaud and Sonenberg 2017). Interestingly, the responses to diverse stressors share common regulatory mechanisms. Thus, up to 49% of the transcriptome, and essentially all mRNAs translated under stress conditions, are regulated by eIF2α phosphorylation, as they have been reported to include uORFs. These mRNAs disproportionately encode proteins involved in pathways that allow cancer cells to adapt to their environment (Calvo et al. 2009 Andreev et al. 2015 Young and Wek 2016 Wek 2018). Furthermore, IRESs, mRNA methylation, and a variety of noncanonical mechanisms of translation initiation maintain protein synthesis in the face of various stresses that inhibit cap-dependent translation (Meyer et al. 2015 Zhou et al. 2015a Lacerda et al. 2017 Robichaud and Sonenberg 2017). How specific subsets of mRNAs are selectively translated in response to each stress is not well understood. Another issue requiring further investigation relates to the fact that inhibition of general translation associated with eIF2α phosphorylation, if persistent, eventually causes cell death (Young and Wek 2016 Robichaud and Sonenberg 2017). Cancer cells may partially escape apoptosis because of the fact that eIF2α phosphorylation promotes the translation of factors promoting its dephosphorylation, resulting in a feedback inhibitory loop (Andreev et al. 2015).

Emerging Oncogenic Advantages of Deregulated Translation

Considering that most cancer deaths are caused by metastatic dissemination, a key emerging concept is the ability of cancer cells to deregulate the translation of prometastatic factors such as matrix metalloproteases, integrins, transcription factors involved in the EMT, and GTPases involved in migration (Silvera et al. 2009 Nasr et al. 2013 Fujimura et al. 2015 Pinzaglia et al. 2015 Robichaud et al. 2015). The importance of cancer-cell-specific translation in the maintenance of cellular energy balance is also becoming clearer, as energy status and protein synthesis are regulated reciprocally to achieve an equilibrium (Proud 2006 Morita et al. 2013 Gandin et al. 2016 Miluzio et al. 2016 Robichaud and Sonenberg 2017). In addition, the interplay between translation and reactive oxygen species (ROS) in cancer cells has recently been revealed. Thus, components of the translation machinery are particularly sensitive to cysteine oxidation by ROS (Chio et al. 2016), whereas the mRNAs encoding key antioxidant proteins possess a motif termed cytosine-enriched regulator of translation (CERT) that confers translation regulation in response to increased eIF4E expression levels (Truitt et al. 2015). Finally, deregulated translation can also promote the expression of proteins involved in DNA repair such as BRCA1, thus enabling the escape from oncogene-induced senescence and resistance to DNA-damaging agents (Badura et al. 2012 Avdulov et al. 2015 Musa et al. 2016). Protein synthesis thus provides a crucial means for cancer cells to disrupt a variety of processes important for all steps of tumor biology.


Volume 184. Advances in Aggregation Induced Emission Materials in Biosensing and Imaging for Biomedical Applications

Advances in Aggregation Induced Emission Materials in Biosensing and Imaging for Biomedical Applications, Volume 184 highlights many aspects of AIE materials that can help future investigators, researchers, students and stakeholders perform research with ease. The book covers a wide range of topics not currently available in a single volume, including sensing of intracellular pH, temperature and viscosity, imaging of cell membrane, cytosol, lysosome, mitochondria, nucleus, DNA, RNA, protein fibrils, cancer and even drug delivery, bacteria, fungi, virus, and many more.

In the action of aggregation induced emission (AIE) photophysical phenomenon, the non-emissive organic/inorganic materials are induced to emit light by the aggregate formation. The AIE phenomenon has appeared as a wand of modern science to convert aggregation-caused quenching (ACQ) materials into AIE material for a wide range of biomedical applications for example biosensing, bioimaging and localization of molecules in order to better understand mechanisms.


Radiobiology and Radiotherapy

The Radiobiology and Radiotherapy Program at Yale Cancer Center comprises a broadly based, multifaceted research effort in radiation therapy, radiation biology, radiological physics, and related areas of tumor biology, including a major effort in DNA damage and repair. Its long-term goal is to improve the treatment of cancer in general and the effectiveness of radiation therapy in particular. Some of the key themes include studies of carcinogenesis, genetic instability and cell growth control elucidation of DNA repair pathways investigation of tumor hypoxia and the impact of hypoxia on cancer therapy preclinical development of radiation sensitizers and DNA repair inhibitors including combination of DNA repair inhibitors with immune therapy molecular correlations with outcomes in radiation therapy health services and disparities research in radiation oncology design and conduct of clinical trials relevant to radiation oncology and improvements in radiation dosimetry, imaging, and delivery.

The program leaders are Dr. Joseph Contessa and Dr. Megan King.


The goals of the Radiobiology and Radiotherapy Program are to:
1. Elucidate pathways of cancer biology that impact radiation therapy.
2. Conduct innovative clinical and translational research to improve radiation therapy