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1.  The cyclin-dependent kinase PITSLRE/CDK11 is required for successful autophagy 
Autophagy  2011;7(11):1295-1301.
(Macro)autophagy is a membrane-trafficking process that serves to sequester cellular constituents in organelles termed autophagosomes, which target their degradation in the lysosome. Autophagy operates at basal levels in all cells where it serves as a homeostatic mechanism to maintain cellular integrity. The levels and cargoes of autophagy can, however, change in response to a variety of stimuli, and perturbations in autophagy are known to be involved in the etiology of various human diseases. Autophagy must therefore be tightly controlled. We report here that the Drosophila cyclindependent kinase PITSLRE is a modulator of autophagy. Loss of the human PITSLRE ortholog, CDK11, initially appears to induce autophagy, but at later time points CDK11 is critically required for autophagic flux and cargo digestion. Since PITSLRE/CDK11 regulates autophagy in both Drosophila and human cells, this kinase represents a novel phylogenetically conserved component of the autophagy machinery.
PMCID: PMC3242795  PMID: 21808150
PITSLRE; CDK11; cyclin-dependent kinase; autophagy; human; Drosophila
2.  DRAM-1 encodes multiple isoforms that regulate autophagy 
Autophagy  2012;8(1):18-28.
Macro(autophagy) is a cellular mechanism which delivers cytoplasmic constituents to lysosomes for degradation. Due to its role in maintaining cellular integrity, autophagy protects against various diseases including cancer. p53 is a major tumor suppressor gene which can modulate autophagy both positively and negatively. p53 induces autophagy via transcriptional activation of damage-regulated autophagy modulator (DRAM-1). We report here that DRAM-1 encodes not just one mRNA, but a series of p53-inducible splice variants which are expressed at varying levels in multiple human and mouse cell lines. Two of these new splice variants, termed SV4 and SV5, result in mature mRNA species. Different from ‘full-length’ DRAM-1 (SV1), SV4 and SV5 do not localize to lysosomes or endosomes, but instead partially localize to peroxisomes and autophagosomes respectively. In addition, SV4 and SV5 can also be found co-localized with certain markers of the endoplasmic reticulum. Similar to SV1, SV4 and SV5 do not appear to be inducers of programmed cell death, but they do modulate autophagy. In summary, these findings identify new autophagy regulators that provide insight into the control of autophagy downstream of p53.
PMCID: PMC3335989  PMID: 22082963
DRAM-1; mRNA splice variants; p53; cell death; autophagy
3.  Oncogene induced sensitization to chemotherapy-induced death requires induction as well as de-regulation of E2F1 
Cancer research  2010;70(10):4074-4080.
The analysis of DNA tumor viruses has provided landmark insights into the molecular pathogenesis of cancer. A paradigm for this field has been the study of the adenoviral E1a protein which has led to identification of proteins such as p300, p400 and members of the retinoblastoma family. Through binding Rb family members, E1a causes deregulation of E2F proteins – an event common to most human cancers and a central pathway in which oncogenes, including E1a, sensitize cells to chemotherapy-induced programmed cell death. We report here, however, that E1a not only causes deregulation of E2F, but importantly that it also causes the post-transcriptional up-regulation of E2F1 protein levels. This effect is distinct from deregulation of E2F1, however, as mutants of E2F1 impaired in pRb binding are induced by E1a and E2F1 induction can also be observed in Rb-null cells. Analysis of E1a mutants selectively deficient in cellular protein binding revealed that induction of E2F1 is instead intrinsically linked to p400. Mutants unable to bind p400, despite being able to deregulate E2F1, do not increase E2F1 protein levels and they do not sensitize cells to apoptotic death. These mutants can, however, be complemented by either knockdown of p400, resulting in restoration of the ability to induce E2F1, or by over expression of E2F1, with both events re-enabling sensitization to chemotherapy-induced death. Due to the frequent deregulation of E2F1 in human cancer, these studies reveal potentially important insights into E2F1-mediated chemotherapeutic responses that may aid the development of novel targeted therapies for malignant disease.
PMCID: PMC2892306  PMID: 20460519
E2F1; E1a; apoptosis; protein-stability; p400
4.  Tumor Antigen LRRC15 Impedes Adenoviral Infection: Implications for Virus-Based Cancer Therapy▿ †  
Journal of Virology  2008;82(12):5933-5939.
Adenoviruses for gene or oncolytic therapy are under development. Notable among these strategies is adenoviral delivery of the tumor suppressor p53. Since all therapeutics have limitations in certain settings, we have undertaken retroviral suppressor screens to identify genes conferring resistance to adenovirus-delivered p53. These studies identified the tumor antigen LRRC15, which is frequently overexpressed in multiple tumor types, as a repressor of cell death due to adenoviral p53. LRRC15, however, does not impede p53 function per se but impedes adenoviral infection. Specifically, LRRC15 causes redistribution of the coxsackievirus-adenovirus receptor away from the cell surface. This effect is manifested in less adenoviral binding to the surfaces of LRRC15-expressing cells. This discovery, therefore, not only is important for understanding adenoviral biology but also has potentially important implications for adenovirus-based anticancer therapeutics.
PMCID: PMC2395123  PMID: 18385238
5.  A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo 
Journal of Clinical Investigation  2007;117(4):1008-1018.
The tumor suppressor p53 is a potent inducer of tumor cell death, and strategies exist to exploit p53 for therapeutic gain. However, because about half of human cancers contain mutant p53, application of these strategies is restricted. p53 family members, in particular p73, are in many ways functional paralogs of p53, but are rarely mutated in cancer. Methods for specific activation of p73, however, remain to be elucidated. We describe here a minimal p53-derived apoptotic peptide that induced death in multiple cell types regardless of p53 status. While unable to activate gene expression directly, this peptide retained the capacity to bind iASPP — a common negative regulator of p53 family members. Concordantly, in p53-null cells, this peptide derepressed p73, causing p73-mediated gene activation and death. Moreover, systemic nanoparticle delivery of a transgene expressing this peptide caused tumor regression in vivo via p73. This study therefore heralds what we believe to be the first strategy to directly and selectively activate p73 therapeutically and may lead to the development of broadly applicable agents for the treatment of malignant disease.
PMCID: PMC1810568  PMID: 17347683

Results 1-5 (5)