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Early embryo Xenopus development
Stills taken from movies located at http://www.xenbase.org/atlas/movies.html.
Scroll to the bottom of the page to find links to these movies.

 

Main areas of research in our laboratory

Tumor biology


Most of the cancer malignancies arise from malfunction of genes that control the cellular responses to DNA-damage as well as cell growth and division. The fact that cancer results from the combined action of multiple oncogenic alterations argues that single-agent therapies will remain the exception. The identification of appropriate targets is based on a detailed understanding of the molecular changes underlying tumor growth and progression. Recent preclinical studies have suggested that radiotherapy in combination with other targeting agents enhances the therapeutic ratio of ionizing radiation alone. However, resistance of tumor cells to chemotherapeutic drugs and radiotherapy represents a major obstacle in anti-cancer therapy. Our research aims to precisely define why some tumors fail to respond to radiotherapy in the first place, and how to interfere with this resistance pathway so that more effective treatment modalities can be developed.

My previous work showed that the cell cycle is arrested and cell death (apoptosis) prevented in Xenopus embryos treated with high doses of ionizing radiation at any time after the mid-blastula transition. This phenotype results from the activation of a concerted number of mechanisms that lead to cell cycle arrest at the G1/S boundary, as observed for most radiation resistant tumors as well. Thus, our research takes advantage of the simplicity of this model organism while using an interdisciplinary approach to identify key fundamental processes and define relevant players relevant to the response of the tumor to ionizing radiation.

Our initial work challenged the long-standing conventional view of radiation-induced apoptosis in which increasing exposure doses results in augmented apoptosis in a biological system, with a threshold below which radiation doses do not cause any significant increase in cell death. The consequences of this belief impact the extent to which malignant diseases and non-malignant conditions are therapeutically treated and how radiation is used in combination with other therapies.

Our research challenges the current dogma of dose-dependent induction of apoptosis and establishes a new paradigm, based a parallel with the photoelectric effect, that the photon energy provides the true threshold for induction of apoptosis in biological systems.

We explored how the energy of individual X-ray photons and exposure time, both components of the total dose, influence the occurrence of cell death in early Xenopus development. Overall, our published results established that the energy of the incident photon determines the outcome of the biological system and, therefore, suggests that biological organisms display properties similar to the photoelectric effect in physical systems. These results provide new insights into how radiation-mediated apoptosis should be understood and utilized for therapeutic purposes.

 

Circadian Clocks and Cancer Biology

A fundamental feature of all living organisms is the presence of two 24h-oscillating cyclic systems. One, the circadian clock, dictates the timing of many physiological responses and provides the cell with information that can be used to anticipate daily environmental changes.

The second highly periodic system is devoted to controlling cell division and mediates the entry into and exit from the cell cycle. We now know that the proper timing of cell division is a major factor contributing to the regulation of normal growth and emerges as a fundamental process in the development of most cancers. Thus, my laboratory investigates some of the basic mechanisms that regulate cell cycle transitions, the contribution of environmental cues to ensure timely progression throughout it, and how both cycles are interlocked at the molecular level. Accordingly, a second area of research focuses in the role of circadian clock proteins as important endogenous factors that contribute to cancer development and progression. Core circadian clock genes are defined as genes whose protein products are necessary components for the generation and regulation of circadian rhythms (from the Latin circa diem, “about a day”). Several studies have shown that about 7% of all circadian-controlled genes regulate either cell-cycle progression or apoptosis. These observations made scientists wonder whether the circadian and cell cycle systems operating within an individual cell might be interlocked by sharing some critical elements. Specifically, our laboratory explores the means by which loss of circadian function impairs apoptosis in response to ionizing radiation, leading to genomic instability and accumulation of damaged cells. The methodologies we use are cellular and molecular biology, structure-based analysis, and systems biology.

Period 2 (Per2) is a transcriptional regulator placed at the core of the circadian clock mechanism that is responsible for generating the negative feedback loop that sustains the clock. Its relevance to human disease is underlined by alterations in its function that impacts numerous biochemical and physiological processes. When absent, it results in the development of various cancers and an increase in the cell’s susceptibility to genotoxic stress. Our most recent findings place the circadian factor Period 2 (Per2) at the heart of the checkpoint response in cells by showing that Per2 interacts directly with the tumor suppressor p53 and its oncogenic regulator Mdm2, thereby participating in the control of downstream p53 signaling. We found that Per2 binds the C-terminus half of human p53 (p53) and forms a stable trimeric complex together with p53’s negative regulator Mdm2. We determined that Per2 binding to p53 prevents Mdm2 from being ubiquitinated and targeting p53 by the proteasome. Accordingly, down-regulation of Per2 expression directly impacts p53 levels whereas its overexpression influences both p53 protein stability and transcription of targeted genes. Overall, our findings place Per2 directly at the heart of the p53-mediated response by ensuring that basal levels of p53 are available to precondition the cell when a rapid, p53-mediated, transcriptional response is needed. Because of the relevance of p53 in checkpoint signaling, we hypothesize that Per2 association with p53 acts as a regulatory module that influences p53’s downstream response to genotoxic stress. Unlike the trimeric complex whose distribution was confined to the nuclear compartment, Per2/p53 was identified in both cytosol and nucleus. At the transcriptional level, a reporter containing the hp21WAF1/CIP1 promoter, a target of p53, remained inactive in cells expressing a stable form of the Per2/p53 complex even when treated with ionizing radiation. Lastly, we established that Per2 directly acts on the p53 node, as checkpoint components upstream of p53 remained active in response to DNA-damage. Quantitative transcriptional analyses of p53 target genes demonstrated that unbound p53 was absolutely required for activation of the DNA-damage response. Our work provides evidence of the mode by which the circadian tumor suppressor Per2 modulates p53 signaling in response to genotoxic stress. More recently, our findings showed that Per2 and p53 rhythms were significantly out-of-phase relative to each other in cell lysates and in purified cytoplasmic fractions. These seemingly conflicting experimental data motivated the use of a combined theoretical and experimental approach focusing on the role played by Per2 in dictating the phase of p53 oscillations. Systematic modeling of all possible regulatory scenarios predicted that the observed phase relationship between Per2 and p53 could be simulated if: i) p53 was more stable in the nucleus than in the cytoplasm, ii) Per2 associates to various ubiquitinated forms of p53, and iii) Per2 mediated p53 nuclear import. These predictions were supported by a 7-fold increase in p53’s half-life in the nucleus and by in vitro binding of Per2 to the various ubiquitinated forms of p53. Lastly, p53’s nuclear shuttling was significantly favored by ectopic expression of Per2 and reduced because of Per2 downregulation. Our combined theoretical/mathematical approach reveals how novel clock regulatory nodes can be inferred from oscillating time course data.

In a third area of research, we investigate the how circadian factors sense metabolic changes and, consequently, act in cell-fate decisions. Here, a multi-technique approach, spanning from the atomic to the cellular level, will be used to elucidate the structural-functional properties of circadian transcription factors. Our objectives are to i) define crosstalk mechanisms among cell cycle, circadian and metabolic components that influence cell cycle transitions ii) study the significance of metabolic signals for circadian rhythmicity and in cell death processes, and iii) determine the structural basis for sensing metabolic changes by circadian proteins. This project will help advance various areas of research by providing a mechanistic explanation for physiological changes accompanying cell division and by elucidating more fully the interplay among cellular mechanisms.

Our Research in the News Across the Globe

YTN Science Channel, South Korea (2016, https://www.youtube.com/watch?v=I8TwPRw-O2s); Augusta Press (2016, http://augustafreepress.com/discovery-take-guesswork-meds-will-work-best/); Asian Scientist (2016, Math reveals the link between the body clock and cancer, http://augustafreepress.com/discovery-take-guesswork-meds-will-work-best/); Herald, South Korea (2016, http://biz.heraldcorp.com/view.php?ud=20161110000169); The Electronic Times, South Korea (2016, Cancer and circadian clock linked through mathematics, http://www.etnews.com/20161110000333); The Science Times (2016, How changes in the biological clock influence cancer incidence in shift workers, http://www.sciencetimes.co.kr/ ); Dong Science, South Korea (2016, KAIST researchers, Impact of biological rhythms in cancer, http://www.dongascience.com/news/view/14676); HelloDD, South Korea (2016, Mathematics unrevealed a link between circadian clock and cancer, http://www.hellodd.com/?md=news&mt=view&pid=59789); SEGYE.com (2016, A correlation between biological clocks and disease onset arise from mathematical modeling, http://www.segye.com/content/html/2016/11/10/20161110003418.html); MBC News (2016, Link between cancer and biological clock found, http://imnews.imbc.com/news/2016/econo/article/4158941_19798.html); The Roanoke Times (2106, Pretty in Pink Fundraiser will benefit breast cancer foundation, http://www.roanoke.com/nrv/community/pretty-in-pink-fundraiser-will-benefit-breast-cancer-foundation/article_9f161b23-185d-5707-ac30-2e9fbf27dff4.html ); ABC 13, WSET (2016, Special Report: Eyes wide shut, A journey to find sleep, http://wset.com/features/special-reports/special-report-eyes-wide-shut-a-sleep-study); Rackspace (2016, Kid’s-STEM, http://racksburg.com/rackspace-sponsors-kids-tech-university/); OurHealth (2016, Bringing health care to sync with our internal clocks, http://www.ourhealthswva.com/); CollegiateTimes, (2015, I just want to cure cancer, http://www.collegiatetimes.com/news/i-just-want-to-cure-cancer-tech-researcher-receives-grant/article_8ea51162-8c17-11e5-8d8c-33fc1a359d14.html);
Youtube (2015, https://youtu.be/K_A_rlHnu_E and https://www.youtube.com/watch?v=_5I1RXaynVQ); Cancer under attack (2015, http://www.vtmag.vt.edu/sum15/cancer-under-attack.html); Pfizer (2015, Cancer protection: Follow the biological clock, http://countering-cancer.tumblr.com/post/116982983041/cancer-protection-follow-the-biological); Circadian rhythms research has linked disruptions in the light-dark cycle to rising cases of breast cancer among night shift workers (2015, http://vbi.vt.edu/news/award-from-national-science-foundation-may-help-researchers-better-understa); Medical News Today (2015, The impact of shift work on health, http://www.medicalnewstoday.com/articles/288310.php); WVTF & RADIO IQ - National Public Radio (2014, Virginia Tech Researchers Study Sleep Cycles & Cancer, http://wvtf.org/post/virginia-tech-researchers-study-sleep-cycles-cancer); WSLS-NBC (2014, Channel 10); The Economic Times (2014, Sleep protein protects from cancer, http://economictimes.indiatimes.com/magazines/panache/sleep-protein-protects-from-cancer/articleshow/45373090.cms); ScienceDaily (2014, Relationship between sleep cycle, cancer found, http://www.sciencedaily.com/releases/2014/12/141203142432.htm); The Frontier Post (2014, Sleep protein protects from cancer, http://www.thefrontierpost.com/2014/12/sleep-protein-protects-from-cancer/); Northwest Pulmonary and Sleep Medicine (2014, Connection between Circadian Rhythms and Cancer, http://www.nwpulmonarysleep.com/Blog.aspx); Spire Healthcare (2014, Sleep-cancer link determined, http://www.spirehealthcare.com/patient-information/health-news/cancer/801764261-sleep-cancer-link-determined/); Virginia Tech News (2014, Gotta get that rhythm: Researchers find a relationship between sleep cycle, cancer incidence, http://www.vtnews.vt.edu/articles/2014/12/120314-fralin-circadianrhythm.html); Bioscience Technology (2014, Relationship between sleep cycle, cancer incidence, http://www.biosciencetechnology.com/news/2014/12/relationship-between-sleep-cycle-cancer-incidence); News Medical (2014, Protein that regulates the body’s sleep cycle may offer cancer protection, http://www.news-medical.net/news/20141204/Protein-that-regulates-the-bodys-sleep-cycle-may-offer-cancer-protection.aspx); Sleep Review (2014, Protein that regulates sleep cycle may offer cancer protection, http://www.sleepreviewmag.com/2014/12/protein-regulates-sleep-cycle-may-cancer-protection/); OregonLive/The Oregonian (2014, Link between sleep and cancer:health news, http://www.oregonlive.com/health/index.ssf/2014/12/scientists_turn_to_crowdsourci.html); Medical News Today (2014, Researchers link altered sleep-wake protein to cancer development, http://www.medicalnewstoday.com/articles/286462.php); Zee News (2014, Sleep protein protects from cancer, http://zeenews.india.com/news/health/health-news/sleep-protein-protects-from-cancer_1509364.html); The Health Site (2014, Research – The link between good sleep and cancer prevention!, http://www.thehealthsite.com/news/research-the-link-between-good-sleep-and-cancer-prevention/); Oman Observer (2014, Sleep protein protects from cancer, http://omanobserver.om/sleep-protein-protects-from-cancer/); ETHealthworld.com (2014, Sleep protein protects from cancer, http://health.economictimes.indiatimes.com/news/diagnostics/sleep-protein-protects-from-cancer/45386212); ???, (2014, ????????????, http://www.ebiotrade.com/newsf/2014-12/2014124171736612.htm); The Times of India (2014, Sleep protein protects from cancer, http://timesofindia.indiatimes.com/life-style/health-fitness/health/Sleep-protein-protects-from-cancer/articleshow/45373417.cms); AugustaFreePress (2014, Virginia Tech researchers find a relationship between sleep cycle, cancer incidence, http://augustafreepress.com/virginia-tech-researchers-find-relationship-sleep-cycle-cancer-incidence/); Dumb-Out (2014, Circadian Protein Disruption Associated With Cancer Risk, http://www.dumb-out.net/circadian-protein-disruption-associated-cancer-risk/12657); Seedoh (2014, Sleep protein protects from cancer, http://www.seedoh.com/%28X%281%29S%28t214yicv2q4jcckn5tqtc0hc%29%29/news/NewsDetail.aspx?ID=2870-Sleep-protein-protects-from-cancer); Ahmedabad Mirror (2014, Sleep protein could help protect us from cancers, http://www.ahmedabadmirror.com/others/scitech/Sleep-protein-could-help-protect-us-from-cancers/articles how/45406694.cms); ?????? online (2014, ????????? ??? ? ??? — ???? ?? ?????, http://www.ahmedabadmirror.com/others/scitech/Sleep-protein-could-help-protect-us-from-cancers/articles how/45406694.cms); Easy Health Options (2014, The work habit that leads to cancer http://easyhealthoptions.com/work-habit-leads-cancer/); eHEALTH (2014, Working night shift may cause Cancer, http://ehealth.eletsonline.com/2014/12/night-duty-may-cause-cancer/); The Roanoke times (2014, Think Pink, http://www.roanoke.com/life/columns_and_blogs/blogs/the_edge/think-pink/article_d24f036b-5ba9-5647-b10c-f61a2b357f60.html?mode=story); American Cancer Society Relay for Life (2014, Virginia Tech, Speaker); Komen Tissue Bank Research Notes (2014, http://komentissuebank.iu.edu/about-ktb/blog/2014/04/17/researcher-chat-with-carla-finkielstein-ph-d/); Youtube (2013, https://www.youtube.com/watch?v=3DqPcAmC75k); Susan Love Research Foundation Report (2013, Facilitating Research); National Science Foundation - Discovery (2013, Studying Molecules that Regulate the Body’s Circadian Rhythms, http://www.nsf.gov/discoveries/disc_summ.jsp?cntn_id=127796&org=NSF); Outbursts - Spotlight on International Faculty Development Program (2013, Fighting Breast Cancer Worldwide, http://www.outreach.vt.edu/Story.aspx?StoryID=917); Virginia Tech - Outreach and International Affairs, (2013, Breast Cancer Researcher Travels to Singapore, http://www.youtube.com/watch?v=3DqPcAmC75k); National Public Radio - Pulse of the Planet (2013); HealthCanal (2013, Studying molecules that regulate the body’s circadian rhythms, http://www.healthcanal.com/medical-breakthroughs/38114-studying-molecules-that-regulate-the-body%E2%80%99s-circadian-rhythms.html); Cancer Today (2013, Standing Strong, http://www.cancertodaymag.org/Summer2013/Pages/Vernal-Branch-Cancer-Survivor-Advocate.aspx?Page=1); Collegiate Times (2013, Associate Professor Finkielstein works toward breast cancer cure, http://www.collegiatetimes.com/lifestyle/people_and_clubs/article_9a7fb30f-7c92-58a7-99c2-f7b7cea09de2.html); AACR video podcasts (2012, Love/Avon Army of Women Panel Discussion, http://www.aacr.org/home/scientists/meetings--workshops/aacr-annual-meeting-2014/previous-annual-meetings/annual-meeting-2012/program/special-sessions.aspx); National Public Radio – With Good Reason (2012, My Saints are Alive Program, aired on Radio IQ and WVTF); National Public Radio – Friday Science (2012); Appalachia Community Cancer Network (2012, http://www.accnweb.com/TrainingProgram-Scholars-Finkielstein.aspx ); The Roanoke Times - The Ticker (2012, http://blogs.roanoke.com/ticker/2012/05/21/virginia-tech-professor-receives-cancer-research-funding/); Science Nation (2012, Body Rhythms and Breast Cancer, http://www.scivee.tv/node/48606); Army of Women – Research transitions: from animal model to human subjects (2012, http://www.armyofwomen.org/Webcast_Updates); USA Today (2012, Indiana breast tissue bank aims for diversity, http://www.usatoday.com/story/news/nation/2012/10/29/indiana-breast-tissue-bank/1666957/, launched the weekend of the superbowl and in collaboration with Susan G. Komen Foundation and the University of Indianapolis) Breast Cancer and Body Rhythms (2011, http://vimeo.com/21816962); Demand Cures TODAY – The Gateway for Cancer Research (2010, http://www.demandcurestoday.org/posts/biologist-carla-finkielstein-receives-minority-scholar-award-source-eurekalertorg); Humanizing the Science of Cancer Research (2009, http://vimeo.com/7446333); Youtube (2010, https://www.youtube.com/watch?v=Q___ARC98MA and https://www.youtube.com/watch?v=fkPRn9rDDMQ); WBDJ Channel 7 (2009, http://virginiatech.tumblr.com/post/227160642/breast-cancer-research); Science Network and in Science Daily (2009, Control of blood clotting by platelets described; provides medical promise, http://insciences.org/article.php?article_id=7697 and http://www.sciencedaily.com/releases/2009/11/091123212551.htm); Drug Discovery and Development (2009, VT Researchers find keys to clotting, http://www.dddmag.com/news/2009/12/vt-researchers-find-keys-clotting).

 

figure

The core feedback loops of the mammalian clock (left) and the clock-controlled pathways (right). Casein kinase 1e (Ck1e); Chryptochrome 1 and 2 (Cry1, Cry2); Period 1, 2 and 3 (Per1, Per2 and Per3); circadian locomotor output cycles kaput protein (Clock); and brain-muscle-ARNT-like protein (Bmal1), and the orphan nuclear receptor rev-erba genes.


Movies illustrating early embryo Xenopus development.
Taken from http://www.xenbase.org/atlas/movies.html. Click thumbnails to view Quicktime movies.

Single Cell to Blastua

Single Cell to Gastrula

 

Gastrulation

Gastrulation

Gastrulation through Neuralation and Talibud

Gastrulation

Neuralation and Elongation

Last Update 9 January 2017