PNAS published our work on kinase dysregulation in multiple inherited cerebellar ataxias Scott Atwood
The genetically heterogeneous Spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of non-receptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degerative disease. Here we reveal that the SFK suppressor Missing-in-Metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically-approved Src inhibitor corrects Purkinje basal firing, and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression. Read More PDF bioRxiv
Journal of Investigative Dermatology accepted for publication our work on primary cilia loss drives basal to squamous cell carcinoma switchingScott Atwood
Basal cell carcinomas (BCCs) rely on Hedgehog (HH) pathway growth signal amplification by the microtubule-based organelle, the primary cilium. Despite naïve tumors responsiveness to Smoothened inhibitors (Smoi), resistance in advanced tumors remains frequent. While the resistant BCCs usually maintain HH pathway activation, squamous cell carcinomas with Ras/MAPK pathway activation also arise, with the molecular basis of tumor type and pathway selection still obscure. Here we identify the primary cilium as a critical determinant controlling tumor pathway switching. Strikingly, Smoi-resistant BCCs possess an increased mutational load in ciliome genes, resulting in reduced primary cilia and HH pathway activation compared to naive or Gorlin patient BCCs. Gene set enrichment analysis of resistant BCCs with a low HH pathway signature reveals increased Ras/MAPK pathway activation. Tissue analysis confirms an inverse relationship between primary cilia presence and Ras/MAPK activation, and primary cilia removal in BCCs potentiates Ras/MAPK pathway activation. Moreover, activating Ras in HH-responsive cell lines confers resistance to both canonical (vismodegib) and non-canonical (aPKC and MRTF inhibitors) HH pathway inhibitors, while conferring sensitivity to MAPK inhibitors. Our results provide new insights into BCC treatment and identify the primary cilium as an important lineage gatekeeper, preventing HH to Ras/MAPK pathway switching.
Journal of Cell Biology published our work on actin polymerization controlling Hedgehog signaling Scott Atwood
Primary cilia are polarized organelles that allow detection of extracellular signals such as Hedgehog (Hh). How the cytoskeleton supporting the cilium generates and maintains a structure that finely tunes cellular response remains unclear. Here we find that regulation of actin polymerization controls primary cilia and Hh signaling. Disrupting actin polymerization, or knockdown of N-WASp/Arp3, increases ciliation frequency, axoneme length, and Hh signaling. Cdc42, a potent actin regulator, recruits both atypical Protein Kinase C iota/lambda (aPKC) and Missing-in-Metastasis (MIM) to the basal body to maintain actin polymerization and restrict axoneme length. Transcriptome analysis implicates the Src pathway as a major aPKC effector. aPKC promotes whereas MIM antagonizes Src activity to maintain proper levels of primary cilia, actin polymerization, and Hh signaling. Hh pathway activation requires Smo, Gli, and Gli1-specific activation by aPKC. Surprisingly, longer axonemes can amplify Hh signaling except when aPKC is disrupted, reinforcing the importance of the Cdc42-aPKC-Gli axis in actin-dependent regulation of primary cilia signaling. Read More PDF
Adam Stabell has joined the lab! Scott Atwood
Adam, a brilliant graduate student, has decided to pursue his thesis work in the lab. Adam received his B.S. in Biochemistry and Molecular Biology from SUNY at Albany where he studied retinoic acid receptor signaling in in salivary gland regeneration in Dr. Melinda Larson's lab. Adam came from the CMB Program and is excited to work on epithelial stem cell function. Welcome to the lab!
Tuyen has been awarded the Susan V. Bryant Graduate Fellowship Award at the Graduate Honors Convocation! Congratulations! Scott Atwood
Dr. Susan V. Bryant is a former Dean of the Ayala School of Biological Sciences, Vice Chancellor for Research, and Executive Vice Chancellor, and has led the School and campus in numerous initiatives. Now retired, she has been an extraordinary mentor and advocate for diversity in the sciences, and continues to play an important role at the School. This fellowship recognizes her overwhelming contributions and is given to doctoral students studying developmental biology with an emphasis in stem cell regeneration.
Taylor has been awarded the SURP fellowship! Congratulations! Scott Atwood
Taylor Levee was awarded the Summer Undergraduate Research Program (SURP) fellowship at UC Irvine for the 2018 summer quarter. SURP provides funding for UCI undergraduates from all disciplines who are conducting summer research projects or creative activities under the guidance of UCI faculty members. The program offers students the opportunity to become immersed in a research topic for a full-time ten-week period, or the equivalent of 400 hours.
Kevin, Ledia, Nikita, and Tanin were awarded Excellence in Research in Biological Sciences! Congratulations! Scott Atwood
The quartet of undergraduates are the first students in the Atwood lab to participate in, and be awarded, Excellence in Research in Biological Sciences. The School of Biological Sciences believes that successful participation in creative research is one of the highest academic goals undergraduates can attain. Students enrolled in Undergraduate Research, and who meet eligibility requirements, have an opportunity to present their scientific data to the academic community at the Undergraduate Research Symposium by participating in the Excellence in Research Program. Those students who successfully complete the program are rewarded with Excellence in Research in Biological Sciences and have their research papers published in this journal.
Journal of Investigative Dermatology published our commentary on genomic stability in basal cell carcinoma Scott Atwood
Sporadic and basal cell nevus syndrome basal cell carcinomas show differential response rates to Smoothened inhibitors. Chiang et al. demonstrate notable decreases in UV-induced mutagenesis, total mutation load, genomic instability, and drug-resistant mutations among basal cell nevus syndrome basal cell carcinomas using whole exome sequencing, which may explain the differences in drug response rates. Read More PDF
Nature Medicine published our work describing GLI co-transcriptional partners SRF-MKL1 as promoters of drug-resistant basal cell carcinoma Scott Atwood
Hedgehog pathway–dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF–MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies. Read More PDF
Baina, Kevin, Nikita, Tanin, Teja, and Yvonne have been awarded the UROP fellowship! Congratulations! Scott Atwood
Six talented undergraduates were awarded the Undergraduate Research Opportunities Program (UROP) fellowship at UC Irvine for the 2017-2018 academic year. The mission of UROP is to integrate undergraduate students into the research culture of the University by providing opportunities for faculty and students to work together on research and creative projects. UROP helps support both the research mission of the University and its educational programs while promoting an undergraduate research culture at UCI. The program fosters collaboration between students, faculty, corporate entities and government agencies to prepare the undergraduate researcher for the challenges of tomorrow. By providing professional environments conducive to research advancement and career skills development, UROP provides students with unique opportunities to develop a wide variety of skills that will be useful in any future career or educational plans. By engaging students in research and creative opportunities, the program hopes to inspire in them a life-long passion for discovery and inquiry-based learning.
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