Table of Contents

Volume 6, Issue 5

  March 1, 2007

  Pages 503 - 625

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 Issue Catalogue (MARC XML)

EXTRA VIEWS

Open Access Article

Inhibitor of NFκB Alpha is a Host Sensor of Coxsackievirus Infection

Marta Saura, Tania R. Lizarbe, Concepcion Rama-Pacheco, Charles J. Lowenstein and Carlos Zaragoza
Pages 503 - 506
http://dx.doi.org/10.4161/cc.6.5.3918
Abstract | PDF

Apoptosis is a host response to viral infection: programmed cell death can limit viral replication. Therefore, the knowledge of pathways by which cells detect viral infection and activate apoptosis may be of considerable interest when developing strategies against viral pathogens. We have shown that cells activate apoptosis in response to Coxsackievirus B3 (CVB3) infection. In an effort to discover how cells detect viral infections, we found that the viral protease 3Cpro cleaves IκBα. Truncated IκBα forms a stable complex with NFκB, translocates to the nucleus, and inhibits NF-κB trans-activation, increasing apoptosis and decreasing viral replication. In contrast, cells in which IκBα expression is reduced are more susceptible to viral infection, showing less apoptosis and more viral replication. IκBα thus acts as a sensor of viral infection. Cleavage of host proteins by pathogen proteases is a novel mechanism by which the host recognizes and responds to viral infection.

Open Access Article

Mig-6, Signal Transduction, Stress Response and Cancer

Yu-Wen Zhang and George F. Vande Woude
Pages 507 - 513
http://dx.doi.org/10.4161/cc.6.5.3928
Abstract | PDF

The mitogen-inducible gene-6 (Mig-6) is an immediate early response gene encoding a nonkinase scaffolding adaptor protein. Mig-6 gene expression can be rapidly and robustly induced under both normal and pathological scenarios by factors including hormones, growth factors, and stresses. However, the precise role of Mig-6 has virtually been a mystery until recently, when we and others discovered that Mig-6 may play important roles in regulating stress response, maintaining homeostasis in tissues like joints or cardiac muscle, and functioning as a tumor suppressor. The discovery that Mig-6 acts as a negative feedback inhibitor of EGF receptor signaling through a direct, physical interaction with the EGF receptor opens a door for understanding the mechanism underlying Mig-6 function. Yet how Mig-6 fine tunes or integrates signal transduction in many pathophysiological situations remains to be determined. Here we will highlight recent discoveries on the role of Mig-6 in stress response, tissue homeostasis, and cancer development; review the transcriptional regulation of Mig-6 expression; share insight into its mechanism in regulating signal transduction; and discuss the paradox of its action modes under different pathophysiological conditions.

Open Access Article

Prospects for Vasculature Reorganization in Sentinel Lymph Nodes

Chao-Nan Qian, James H. Resau and Bin Tean Teh
Pages 514 - 517
http://dx.doi.org/10.4161/cc.6.5.3931
Abstract | PDF

Primary tumors can induce vasculature and lymph channel reorganizations within sentinel lymph nodes before the arrival of cancer cells. The key blood vessels in such nodes that are remodeled are high endothelial venules (HEVs). The morphological alteration of HEVs in the presence of a cancer, coupled with the increased proliferation rate of the endothelial cells, results in a functional shifting of HEVs from immune response to blood-flow carrier. This tumor-induced reorganization is quite different from an endotoxin-induced inflammatory vasculature alteration. We review some of the accepted doctrines on lymph flow and lymphatic metastasis in light of this reorganization. More investigations are needed to elucidate the molecular mechanisms underlying the morphological and functional alteration of HEVs, the fluid exchanges between lymph and blood, the microenvironmental preparation for cancer cells to survive and expand in the lymph node, and the detail process of further distant dissemination of cancer cells from the lymph nodes. Further study of this pathological process may help to explain some clinical phenomena, and should aid in developing novel therapeutics and prevention strategies against cancer metastasis.




PERSPECTIVES

Open Access Article

Survivin’s Dual Role: An Export’s View

Shirley K. Knauer, Wolf Mann and Roland H. Stauber
Pages 518 - 521
http://dx.doi.org/10.4161/cc.6.5.3902
Abstract | PDF

Survivin is proposed to function as a mitotic regulator and an apoptosis inhibitor during development and pathogenesis. As such, survivin has aroused keen interest in disparate areas of basic and translational research. Survivin acts as a subunit of the chromosomal passenger complex (CPC), composed of the mitotic kinase Aurora-B, Borealin 5 and INCENP, and is essential for proper chromosome segregation and cytokinesis. Our recent findings indicate that the nuclear export receptor Crm1 is critically involved in tethering the CPC to the centromere by interacting with a leucine-rich nuclear export signal (NES), evolutionary conserved in all mammalian survivin proteins. In addition, the survivin/Crm1 interaction 10 seems to be required for the cytoprotective activity of survivin, because export deficient survivin fails to protect tumor cells against cancer therapy-induced apoptosis. These findings appear of clinical relevance since preferential nuclear localization of survivin turned out to be a favorable prognostic factor in cancer patients. Besides emphasizing the functional significance of the Crm1/survivin interface, we suggest to exploit the pharmacogenetic 15 interference with survivin’s export as a novel strategy to antagonize survivin’s activity.

Open Access Article

Sphingosine-1-Phosphate Metabolism and Intestinal Tumorigenesis: Lipid Signaling Strikes Again

Babak Oskouian and Julie Saba
Pages 522 - 527
http://dx.doi.org/10.4161/cc.6.5.3903
Abstract | PDF

Sphingolipids are an evolutionary conserved class of membrane lipids synthesized by all eukaryotic cells. The biological functions of sphingolipids are diverse, encompassing structural roles through their participation in membrane lipid rafts, and informational roles via the involvement of their metabolites in signal transduction pathways. An important sphingolipid metabolite is sphingosine-1-phosphate (S1P), which acts through G protein-coupled receptors present on mammalian cells, thereby stimulating cell proliferation, angiogenesis and inhibiting apoptosis. The main enzyme responsible for S1P synthesis, sphingosine kinase 1 (Sphk1), behaves as an oncogene in experimental systems and is required for polyp enlargement in the Min mouse model of intestinal tumorigenesis. S1P is irreversibly degraded by S1P lyase (SPL), an enzyme that is highly expressed in enterocytes, where it is involved in metabolism of dietary sphingolipids. Forced expression of SPL sensitizes human cells to various stressful stimuli and enhances apoptotic cell death. SPL expression is induced in response to DNA damaging agents in a time- and concentration-dependent manner. On the other hand, SPL is downregulated in human colon cancers and in Min mouse adenomas compared to adjacent uninvolved tissues. These observations suggest that SPL, like Sphk1, may play a role in tumorigenesis. Added support for this notion comes from the fact that S1P-specific antibodies slow tumor progression and angiogenesis in murine xenograft and allograft models. Together, these recent studies have established a link between S1P signaling, metabolism and carcinogenesis that may have implications regarding colon cancer screening, dietary chemoprevention and therapeutics.

Open Access Article

Interfering with MAP Kinase Docking Interactions: Implications and Perspectives for the p38 Route

Federico Mayor, Jr., Maria Jurado-Pueyo, Pedro M. Campos and Cristina Murga
Pages 528 - 533
http://dx.doi.org/10.4161/cc.6.5.3920
Abstract | PDF

Docking interactions are key to understand the dynamic assembly of signal transduction complexes in the cell. In particular, the docking domain (D domain)-dependent interactions described so far for several MAPK routes are essential to specify the upstream regulators, downstream mediators and also inactivators that complex with the p38, JNK and ERK proteins. In addition to contributing to the maintenance of the linearity and specificity of these pathways, novel data have revealed that docking contacts also regulate the activity, subcellular distribution and substrate selection of each MAPK. Moreover, phosphorylation inside or around a docking domain is emerging as a novel mechanism of regulation of MAPK association with cellular partners, suggesting new potential strategies for the design of selective MAPK inhibitors. Here, we discuss these novel data and the biochemical and cellular implications they may have with specific emphasis on the p38 route.

Open Access Article

p38 MAP Kinase Regulates Stem Cell Apoptosis in Human Hematopoietic Failure

Li Zhou, Joanna Opalinska and Amit Verma
Pages 534 - 537
http://dx.doi.org/10.4161/cc.6.5.3921
Abstract | PDF

Myelodysplastic syndromes (MDS) are clonal stem cell disorders that lead to ineffective hematopoiesis and are common causes of low blood counts in the elderly. The exact molecular mechanisms regulating increased stem apoptosis in these disorders are not well defined. p38 MAPK activation is important in regulating the growth inhibitory signals of TNF-α, TGF-β and Interferons on human hematopoiesis. Our findings show that p38 MAPK is overactivated in myelodysplasia bone marrows and regulates hematopoietic stem cell apoptosis. Inhibition of p38 MAPK by genetic or pharmacologic means decreases apoptosis and stimulates in vitro hematopoiesis from primary MDS hematopoietic progenitors. These studies point to the potential efficacy of selective p38α inhibitor, SCIO-469, in human bone marrow failure.

Open Access Article

Inhibition of VEGF Signaling Pathways in Multiple Myeloma and Other Malignancies

Klaus Podar and Kenneth C. Anderson
Pages 538 - 542
http://dx.doi.org/10.4161/cc.6.5.3922
Abstract | PDF

Due to its direct effects on endothelial cells, circulatory endothelial progenitor cells, hematopoietic stem cells, immune cells, osteoclasts, osteoblasts, and neurons, vascular endothelial growth factor (VEGF) is linked to tumor cell development, progression, metastatic osteolysis, and drug resistance, as well as clinical features such as metastatic osteolysis. Importantly, recent advances in the understanding of mechanisms of action of antiangiogenic drugs/ VEGF-inhibitors have fundamentally changed treatment regimens in cancer. VEGF plays a key role not only in solid tumors but also in hematologic malignancies, including multiple myeloma (MM). Despite recent advances in our understanding of MM pathogenesis and novel therapies (bortezomib and lenalidomide), it remains incurable. Our own and others’ work suggest that VEGF-inhibitors e.g. the small-molecule VEGF receptor inhibitor pazopanib, may also improve patient outcome in MM.

Open Access Article

Lymphoid Progenitors as Candidate Cancer Stem Cells in AML: New Perspectives

Aniruddha J. Deshpande and Christian Buske
Pages 543 - 545
http://dx.doi.org/10.4161/cc.6.5.3968
Abstract | PDF

Mouse models have demonstrated that both hematopoietic stem cells (HSCs) as well as downstream myeloid progenitors can be targets of transformation in AML. We recently showed in a murine model of the CALM/AF10 fusion gene positive leukemia, that progenitors with lymphoid characteristics can be leukemic stem cell (LSC) candidates in AML. We could demonstrate that the LSC candidate in the CALM/AF10 murine model was positive for the lymphoid associated surface antigen B220, which was not expressed by the leukemic bulk or the normal HSC pool. This offers the intriguing possibility to target the LSCs with antibodies that spare the normal stem cell.

Open Access Article

Telomerase: Going Beyond the Ends

David De Semir, Mehdi Nosrati, Shang Li and Mohammed Kashani-Sabet
Pages 546 - 549
http://dx.doi.org/10.4161/cc.6.5.3980
Abstract | PDF

To date, the major function attributed to telomerase has been the elongation of telomeres. Recent studies have assigned new biochemical properties to telomerase by implicating a role in tumor metastasis and cellular differentiation by virtue of its modulation of novel cell signaling pathways such as glycolysis. In this Perspective we will discuss these recent results that have provided additional insight into the involvement of telomerase in cellular processes other than telomere maintenance at chromosome ends.




REVIEW

Open Access Article

Oncogenes in Myeloproliferative Disorders

Ayalew Tefferi and D. Gary Gilliland
Pages 550 - 566
http://dx.doi.org/10.4161/cc.6.5.3919
Abstract | PDF

Myeloproliferative disorders (MPDs) constitute a group of hematopoietic malignancies that feature enhanced proliferation and survival of one or more myeloid lineage cells. William Dameshek is credited for introducing the term “MPDs” in 1951 when he used it to group chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) under one clinicopathologic category. Since then, other myeloid neoplasms have been added to the MPD member list: chronic neutrophilic (CNL), eosinophilic (CEL), and myelomonocytic (CMML) leukemias; juvenile myelomonocytic leukemia (JMML); hypereosinophilic syndrome (HES); systemic mastocytosis (SM); and others. Collectively, MPDs are stem cell-derived clonal proliferative diseases whose shared and diverse phenotypic characteristics can be attributed to dysregulated signal transduction—a consequence of acquired somatic mutations. The most recognized among the latter is BCR-ABL, the disease-causing mutation in CML. Other mutations of putative pathogenetic relevance in MPDs include: JAK2V617F in PV, ET, and PMF; JAK2 exon 12 mutations in PV; MPLW515L/K in PMF and ET; KITD816V in SM; FIP1L1-PDGFRA in CEL-SM; rearrangements of PDGFRB in CEL-CMML and FGFR1 in stem cell leukemia-lymphoma syndrome; and RAS/PTPN11/NF1 mutations in JMML. This increasing repertoire of mutant molecules has streamlined translational research and molecularly targeted drug development in MPDs.




BRIEF REPORTS

Open Access Article

Long-Lasting Expression of HO-1 Delays Progression of Type I Diabetes in NOD Mice

Ming Li, Stephen Peterson, Daniel Husney, Muneo Inaba, Kequan Guo, Attallah Kappas, Susumu Ikehara and Nader G. Abraham
Pages 567 - 571
http://dx.doi.org/10.4161/cc.6.5.3917
Abstract | PDF

Heme oxygenase-1 (HO-1) is crucial in regulating oxidative injury. The present study was designed to assess whether HO-1 upregulation by cobalt protoporphyrin IX (CoPP) moderates or prevents the diabetic state in non-obese diabetic (NOD) mice, an animal model for Type 1 diabetes (T1D). HO-1 expression and HO activity were upregulated in the pancreas by the intermittent administration of CoPP. This was associated with decreases in blood glucose and pancreatic O2-, but increased pAKT and BcL-XL and cell survival. A considerable number of beta cells were preserved in the islets of CoPP-treated NOD mice, while none were found in untreated diabetic mice. The number of CD11c+ dendritic cells was decreased in the pancreas of CoPP-treated NOD mice (p<0.05). These novel findings provide a link between the increase in HO-1 and a decrease in infiltrated CD11c+ dendritic cells, and suggest that induction of HO-1 activity can be used to enhance cell survival and moderate the diabetic state in T1D.

Open Access Article

G2 Checkpoint Kinase Inhibitors Exert Their Radiosensitizing Effects Prior to the G2/M Transition

Christopher M. Sturgeon and Michel Roberge
Pages 572 - 575
http://dx.doi.org/10.4161/cc.6.5.3926
Abstract | PDF

Chemical inhibitors of the G2 checkpoint can sensitize p53-defective cancer cells to DNA damage and several are in preclinical or clinical development. These compounds are commonly thought to increase killing at the G2/M transition by forcing cells to divide with unrepaired DNA. We examined the effects of the ATM/ATR inhibitor caffeine and the Chk1 inhibitor isogranulatimide on the clonogenic survival of two p53-defective cell lines, MCF7-mp53 and HCT-116 p53-/- cells, when added at different times after exposure to ionizing radiation. Exposure 16-24 h after irradiation, when G2 arrest is maximal, forced premature entry into mitosis but increased clonogenic survival. Radiosensitization occurred mostly upon exposure between 2 and 16 h after irradiation, correlating with S-phase traversal. These results suggest that inhibition of the S phase activities of ATM/ATR and Chk1 may be more relevant to radiosensitization of p53-defective cells than G2 checkpoint abrogation and that careful scheduling of combination treatments might be required for synergistic antitumour effects in vivo.

Open Access Article

Oxidative Stress Overrides the Spindle Checkpoint

Vincenzo D'Angiolella, Concetta Santarpia and Domenico Grieco
Pages 576 - 579
http://dx.doi.org/10.4161/cc.6.5.3934
Abstract | PDF

Aneuploidy, an abnormal chromosome set, can ensue from failure of the spindle checkpoint, the safeguard mechanism that halts anaphase onset until mitotic spindle assembly. Inefficiency of cells to maintain the normal chromosome set across cell generations has been linked to tumorigenesis and senescence. Here we show that oxidative stress overrides the spindle checkpoint mechanism. Oxidant challenge of checkpoint-arrested cells led to proteolysis of the anaphase inhibitor securin and mitotic cyclins. This appeared consequent to loss of cyclin B-cdk1 activity caused by oxidant-induced reversal of cdk1 inhibitory phosphorylation. These observations may provide a link between aneuploidy occurrence and oxidative stress.




REPORTS

Open Access Article

Glycogen Synthase Kinase - 3 Phosphorylates and Regulates the Stability of p27kip1 Protein

Milan Surjit and Sunil K. Lal
Pages 580 - 588
http://dx.doi.org/10.4161/cc.6.5.3899
Abstract | PDF

p27 Kip1 is a critical regulator of the eukaryotic cell cycle. It acts as a check point protein and regulates cell cycle progression at the G1 and G1/S phase as well as predominantly blocks cell cycle progression in the absence of growth factors. Intracellular turnover of p27 is tightly regulated at the level of translation as well as by posttranslational modification. The mechanism by which p27 protein is rapidly degraded during the G1 and G1/S phase transition is well characterized. However, the process by which p27 remains extremely stable in the absence of growth factors remains unknown. Here, we report that GSK-3 dependent phosphorylation of p27 protein is essential for its enhanced stability. p27 protein harbours 2 functional GSK-3 phosphorylation sites at the C- terminus, which was found to be effectively phosphorylated by the cognate enzyme both in vitro and in vivo. Combined with earlier observation which shows that it phosphorylates and triggers cyclin D degradation; GSK-3 now appears to be a central mediator of the cell-cycle regulatory network, where it acts as a two-way switch, phosphorylating and targeting pro-proliferative factors for degradation on one hand and simultaneously phosphorylating and stabilizing an anti-proliferative factor on the other hand. This dual mode of activity may doubly ensure that cell cycle progression is aptly prohibited under conditions of limited growth factor availability.

Open Access Article

Apaf1 in Chronic Myelogenous Leukemia (CML) Progression: Reduced Apaf1 Expression is Correlated with a H179R p53 Mutation During Clinical Blast Crisis

Osnat Ashur-Fabian, Konstantin Adamsky, Luba Trakhtenbrot, Yoram Cohen, Pia Raanani, Izhar Hardan, Arnon Nagler, Gideon Rechavi and Ninette Amariglio
Pages 589 - 594
http://dx.doi.org/10.4161/cc.6.5.3900
Abstract | PDF

Chronic myelogenous leukemia (CML) is a stem cell disorder that eventually progresses to a blast crisis phase (BC) characterized by distorted apoptotic pathways. The exact mechanism leading to failure in apoptotic pathways during CML progression is unclear. In view of the central role of p53 and apaf1 in the apoptotic machinery we examined six human paired chronic and BC phases samples for their expression.

Real-time PCR (RQ-PCR) experiments showed an elevation of p53 mRNA in all patients during transition to BC. However, elevation of apaf1 during BC was observed in five patients only. In contrast, one patient displayed a significant 11.5-fold reduction of apaf1 expression during the transition to BC. No apaf1 promoter methylation was observed. The reduced apaf1 expression was accompanied by a trans-dominant point mutation (H179R) in one p53 allele and the loss of the other. This mutant p53, when tested using functionality assays, was unable to activate apaf1, consequently explaining the reduced expression observed in this patient. Furthermore, the same mutant failed to activate either genes involved in apoptotic or cell cycle arrest pathways, and can be considered as a complete loss of function mutation. This specific mutation was reported in several types of cancer, but was not implicated in CML. To conclude, in this study we have demonstrated mRNA elevation of p53 and apaf1 during CML blast crisis, indicating that genes and proteins involved in cellular apoptosis might be involved in disease progression/response to therapy. Moreover, the mutated p53 discovered in the patient exhibiting lowered apaf1 expression provides, in a clinical case, the first correlation between p53 and apaf1 transcription regulation in humans.

Open Access Article

A Dominant Role for p53-Dependent Cellular Senescence in Radiosensitization of Human Prostate Cancer Cells

Brian D. Lehmann, James A. McCubrey, Holly S. Jefferson, Matthew S. Paine, William H. Chappell and David M. Terrian
Pages 595 - 605
http://dx.doi.org/10.4161/cc.6.5.3901
Abstract | PDF

Because p53 inactivation may limit the effectiveness of radiation therapy for localized prostate cancer, it is important to understand how this gene regulates clonogenic survival after an exposure to ionizing radiation. Here, we show that premature cellular senescence is the principal mode of cell death accounting for the radiosensitivity of human prostate cancer cell lines retaining p53 function. Alternative stress response pathways controlled by this tumor suppressor, including cell cycle arrest, DNA damage repair, mitotic catastrophe and apoptosis, contributed significantly less to radiation-induced clonogenic death. Using a dominant negative C-terminal fragment of p53, we present the first evidence that a complete loss of endogenous p53 function is sufficient to limit the irradiation-induced senescence and clonogenic death of prostate cancer cells. Conversely, inheritance of wild-type p53 by prostate cancer cells lacking a functional allele of this gene (i.e., DU145) significantly increases clonogenic death through p53-dependent cellular senescence and apoptotic pathways. Our data provide evidence that mutations of even one p53 allele may be sufficient to alter their clonogenic fate. In addition, they support the idea that the p53 pathway can be used as a specific target for enhancing the radiosensitivity of prostate cancer cells. Activation of p53 by the drug nutlin-3 is shown to be an effective radiosensitizer of prostate cancer cells retaining functional alleles of p53 and this effect was entirely attributable to an increased induction of p53-dependent cellular senescence.

Open Access Article

XRCC3 Depletion Induces Spontaneous DNA Breaks and p53-Dependent Cell Death

Martin Loignon, Lilian Amrein, Michael Dunn and Raquel Aloyz
Pages 606 - 611
http://dx.doi.org/10.4161/cc.6.5.3923
Abstract | PDF

In vertebrate cells, Xrcc3 initiates the repair of exogenous induced-DNA breaks during S and G2/M phases of the cell cycle by homologous recombination. However, much less is known of the role of Xrcc3 in the response to spontaneous DNA breaks. Using a siRNA approach, we show that depletion of XRCC3 inhibits the proliferation of MCF7 breast cancer cells. This inhibition of replication coincides with the accumulation of DNA breaks, as shown by the comet assay. Cell cycle specific analysis of γH2AX expression shows that S and G2/M phase cells express the highest fraction of γH2AX positive cells. This is consistent with replication-dependent accumulation of DNA breaks and deficient homologous recombination. While the induction of γH2AX is followed by cell death in parental cells, a p53 knockdown derivative becomes more resistant to XRCC3 depletion-induced death without changes in the levels of γH2AX. These results show that XRCC3 is required for the proliferation of MCF7 cells, and that decrease in its expression leads to the accumulation of DNA breaks and the induction of p53-dependent cell death.

Open Access Article

Cell Division and Maintenance of Epithelial Integrity in the Deafened Auditory Epithelium

Young Ho Kim and Yehoash Raphael
Pages 612 - 619
http://dx.doi.org/10.4161/cc.6.5.3929
Abstract | PDF

Quiescence is among the hallmarks of the sensory epithelium of the cochlea. When auditory sensory cells (hair cells) degenerate they are not replaced, and therefore hearing loss is permanent. Cochlear hair cells are susceptible to several types of lesions, including aminoglycoside antibiotics. The application of the aminoglycoside neomycin in the inner ear mimics cases of severe hair cell loss and leads to collapse of the cochlear epithelium. We now report that in mature guinea pig cochleae injected with neomycin, the remaining non-sensory cells undergo a robust proliferative response. p27Kip1, an inhibitor of cell cycle in the cochlea, was present in non-dividing cells and absent during mitosis. Dividing cells retained their tight junction complexes and maintained the structural confluence of the auditory epithelium during cell division. The plane of mitosis was invariably parallel to the luminal surface. These results indicate that the flat epithelium of the cochlea can down-regulate p27Kip1 and divide after a severe lesion and suggest that the cell divisions assist in maintaining the epithelial confluence throughout the cochlea. Presence of mitosis in the tissue presents therapeutic opportunities for gene transfer and stem cells therapies.

Open Access Article

Role of the CDKN1A/p21, CDKN1C/p57, and CDKN2A/p16 Genes in the Risk of Atherosclerosis and Myocardial Infarction

Isabel Rodríguez, Eliecer Coto, Julián R. Reguero, Pelayo González, Vicente Andrés, Iñigo Lozano, María Martín, Victoria Alvarez and César Morís
Pages 620 - 625
http://dx.doi.org/10.4161/cc.6.5.3927
Abstract | PDF

Atherosclerotic is characterised by excessive proliferation of neointimal leukocytes and vascular smooth muscle cells (VSMCs). In mice, the manipulation of cell cycle inhibitors such as CDKN1B (p27) and CDKN1A (p21) modifies the risk of developing atherosclerosis. In humans, CDKN1A, CDKN1B, and CDKN1C (p57) are differentially expressed in normal versus atherosclerotic vessels. A DNA-polymorphism within the CDKN1B promoter has been associated with myocardial infarction (MI). In the present study, we analysed the effect of CDKN1A, CDKN1C, and CDKN2A (p16) polymorphisms on MI-risk. A total of 316 patients (all male, <55 years) and 434 controls were genotyped, and the allele and genotype frequencies were compared between the two groups. Two CDKN1C polymorphisms, a promoter GT-repeat and a variable number of repeats of the amino acid PAPA-motif, were associated with MI. The presence of two alleles ≤11-repeats (9/11, 10/11, and 11/11 genotypes) was significantly less frequent among patients (p<0.001). This difference was also significant when analyzing the subpopulation of smokers (p=0.004), suggesting a protective role for these low-repeat genotypes (OR=0.49, 95%CI=0.32-0.73). The PAPA-BB homozygotes were significantly less frequent in patients, but this could be attributed to a linkage disequilibrium between the 11-repeats and B alleles. No significantly different frequencies between patients and controls for the four CDKN1A (-1026A/G, -754G/C, -369G/C, and Ser31Arg) and the three CDKN2A (-523 G/A, +22 G/A, and Ala148Thr) polymorphisms was found. In conclusion, we provide here genetic evidence for the association between DNA-variants in the CDKN1C/p57 gene and the risk of atherosclerosis and MI.