[Status and clinical response of fertility preservation in young patients with breast cancer].

Cancer treatments may improve the long-term survival rate of young patients with breast cancer, but also lead to a decrease in fertility. With the younger incidence of breast cancer in China, the fertility needs of this group have received more attention, and fertility preservation technology suitable for cancer patients is developing continuously. However, there are still many problems in the implementation of fertility preservation for young breast cancer patients in China. Patients and breast surgeons have insufficient understanding and conservative attitudes towards fertility preservation technology. And there is a lack of reproductive experts in the treatment process. What's more, the long-term follow-up and information management of patients undergoing fertility preservation are defective. In response to the above, this paper discusses how to deal with patients with potential reproductive needs in clinical practice from the perspective of breast surgeons. The first is to improve their own understanding of fertility preservation, such as the progress of relevant technologies and applicable population, when to intervene, when and how to get pregnant after cancer treatment. Secondly, education for patients must be strengthened, which should include not only fertility preservation, but also scientific contraceptive methods during cancer treatment and treatment measures for unexpected pregnancy. Finally, hospitals and relevant units should standardize the multidisciplinary team of breast cancer, and strengthen the comprehensive management of young breast cancer patients, thus to provide young breast cancer patients with more scientific cancer treatment programs and more reproductive opportunities.

[Multidisciplinary cooperation strengthens individualized management of breast cancer in pregnancy].

As the pregnant patient with breast cancer is in a special physiological period, both the efficacy of mother and the safety of developing fetus should be considered during the whole process of diagnosis and treatment. It is particularly important for multidisciplinary teams including breast, obstetrics and nursing departments to make a secure and effective individualized plan for those in different gestational week and different stages of breast cancer development. Pregnancy risk assessment and whole-process multidisciplinary case management mode for breast cancer during pregnancy are helpful for the early detection of abnormal health status of pregnant women and fetuses, enabling rapid and efficient treatment, reducing the occurrence of adverse medical events, and maximizing the safety of pregnant women and fetuses. Obstetricians should pay attention to the chief complaints of pregnant women and conduct regular breast ultrasound examinations. Once anything suspicious is found, breast surgeons need to take charge of a multidisciplinary discussion. Not only should the multidisciplinary collaborative outpatient clinic determine the treatment plan for breast cancer during pregnancy, but also the concept of multidisciplinary collaboration should be incorporated into the follow-up treatment process, including active surgical treatment, selection of neoadjuvant chemotherapy and adjuvant chemotherapy, avoidance of endocrine therapy, targeted therapy and radiotherapy, and adherence to multidisciplinary follow-up, etc. Multidisciplinary case management of breast cancer during pregnancy is necessary and feasible, and more prospective clinical studies need to be carried out to help improve clinical diagnosis and treatment strategies.

Sudden-onset unilateral ptosis induced by pituitary Macroadenoma, with false-positive jolly and neostigmine tests.

The development of ptosis as a consequence of pituitary tumor is an exceptionally rare occurrence. Here, we describe the case of sudden-onset unilateral ptosis induced by pituitary macroadenoma. The condition was characterized by false-positive Jolly and neostigmine tests. These findings mimic oculomotor nerve palsy and make the correct diagnostics rather challenging. The case points to the fact that patients with acquired ptosis need detailed neuroophthalmological examination.

[Thoughts on optimizing the breast cancer screening strategies and implementation effects].

Reasonable and effective breast cancer screening can make early diagnosis of breast cancer, improve the cure rate, prolong survival and improve the patients' quality of life. China has made preliminary exploration and attempt in breast cancer screening, however, there are still some problems that have not been solved in terms of the proportion of opportunistic screening, the selection of screening targets, methods and frequency, and the judgment of screening results. Therefore, this article analyzes the above problems in details, and presents some thoughts and recommendations on how to optimize the breast cancer screening strategies and implementation effects in China, from the experience of clinical practice, under the background of constantly emerging new research results and techniques and the rapid development of artificial intelligence, that is, to adjust measures to local conditions, provide personalized strategies, achieve precise screening, preach and educate, ensure health insurance coverage, improve quality control, offer technical support and employ artificial intelligence.

[Retrospective analysis of diagnosis and treatment of breast cancer in pregnancy].

Objective: To investigate the principles of diagnosis and treatment of breast cancer during pregnancy. Methods: Clinical data of patients with breast cancer during pregnancy admitted to Obstetrics and Gynecology Hospital of Fudan University between January 2012 to July 2017 were analyzed retrospectively. A total of 17 patients were diagnosed with breast cancer in pregnancy, the median age was 32 years (range from 25 to 45 years old), pathological staging revealed 2 patient with stage 0, 1 with stage Ⅱa, 7 with stage Ⅱb, 1 with stage Ⅲa, 2 with stage Ⅲc, 4 with stage Ⅳ. Results: Thirteen patients received surgical treatment in pregnancy, the gestational age at surgery was (27.7±4.6) weeks; 2 patients with ductal carcinoma in situ received mastectomy, 11 patients with breast cancer underwent modified radical mastectomy. In patients undergoing surgery during pregnancy, no prophylactic contractions were used in 4 patients who had been treated earlier, there were 2 patients with frequent contractions within 24 hours after operation in these patients. Follow-up 9 patients were given oral nifedipine to prevent contractions, no obvious contractions occurred after the operation. Seven patients received chemotherapy during pregnancy; the chemotherapy of 4 cases of triple negative breast cancer was weekly paclitaxel sequential epirubicin and cyclophosphamide, the chemotherapy of the other three patients was docetaxel sequential epirubicin and cyclophosphamide. Fifteen patients underwent cesarean section to terminate pregnancy, 2 patients underwent spontaneous labor. The gestational age of birth was (36.9 ±1.3) weeks. Less than 35 weeks of termination of pregnancy occurred in one patient, the fetus was delivered to the neonatal intensive care unit due to neonatal respiratory distress syndrome, and suffered from congenital dysaudia. The prognosis of the other 16 survived infants was good. The median follow-up time was 10 months (range from 4 to 27) months, in 13 patients of stage 0 to Ⅲc, one patient were diagnosed with bone metastasis at 12 months after surgery, the remaining 12 patients had no disease progression, the progression free survival rate was 12/13, the overall survival rate was 13/13. Among the 4 patients with stage Ⅳ, one died in 7 months after delivery, one had new liver metastasis in 8 months after delivery. The remaining 2 patients were in stable condition. Conclusions: Breast cancer in pregnancy can be treated effectively, multidisciplinary cooperation and detailed assessment of maternal-fetal risks and benefits are necessary. Chemotherapy during pregnancy is safe for maternal-fetal, but it needed a large sample of clinical studies and long-term follow-up. The neonatal outcome was associated with gestational age, and therefore premature delivery was avoided as much as possible during treatment.

Thrombin Activates Latent TGFß1 via Integrin αvß1 in Gingival Fibroblasts.

Transforming growth factor ß (TGFß) regulates cell proliferation, differentiation, migration, apoptosis, and extracellular matrix production. It also plays a pivotal role in the pathogenesis of gingival overgrowth. Thrombin is a key player in tissue repair, remodeling, and fibrosis after an injury, and it exerts profibrotic effects by activating protease-activated receptors. Connective tissue growth factor (CTGF or CCN2) modulates cell adhesion, migration, proliferation, matrix production, and wound healing. It is overexpressed in many fibrotic disorders, including gingival overgrowth, and it is positively associated with the degree of fibrosis in gingival overgrowth. In human gingival fibroblasts, we previously found that TGFß1 induced CCN2 protein synthesis through c-jun N-terminal kinase and Smad3 activation. Thrombin stimulates CCN2 synthesis through protease-activated receptor 1 and c-jun N-terminal kinase signaling. Curcumin inhibited TGFß1- and thrombin-induced CCN2 synthesis. In this study, we demonstrated that thrombin and protease-activated receptor 1 agonist SFLLRN induced latent TGFß1 activation and Smad3 phosphorylation in human gingival fibroblasts. Pretreatment with a TGFß-neutralizing antibody, TGFß type I receptor inhibitor SB431542, and Smad3 inhibitor SIS3 inhibited approximately 86%, 94%, and 100% of thrombin-induced CCN2 synthesis, respectively. Furthermore, blocking integrin subunits αv and ß1 with antibodies effectively inhibited SFLLRN-induced Smad3 phosphorylation and CCN2 synthesis and increased activated TGFß1 levels; however, similar effects were not observed for integrins αvß3 and αvß5. These results suggest that protease-activated receptor 1-induced CCN2 synthesis in human gingival fibroblasts is mediated through integrin αvß1-induced latent TGFß1 activation and subsequent TGFß1 signaling. Moreover, curcumin dose dependently decreased thrombin-induced activated TGFß1 levels. Curcumin-inhibited thrombin-induced CCN2 synthesis in human gingival fibroblasts is caused by the suppression of latent TGFß1 activation.

NADPH Oxidase 4 Mediates TGFß1-induced CCN2 in Gingival Fibroblasts.

Transforming growth factor ß (TGFß) plays a central role in the pathogenesis of gingival overgrowth (GO). Connective tissue growth factor (CTGF; or CCN2) is induced by TGFß in human gingival fibroblasts (HGFs) and is overexpressed in GO tissues. CCN2 creates an environment favorable for fibrogenesis and is required for the maximal profibrotic effects of TGFß. We previously showed that Src, JNK, and Smad3 mediate TGFß1-induced CCN2 protein expression in HGFs. Moreover, Src is an upstream signaling transducer of JNK and Smad3. Recent studies suggested that NADPH oxidase (NOX)-dependent redox mechanisms are involved in mediating the profibrotic effects of TGFß. In this study, we demonstrated that TGFß1 upregulated NOX4 protein expression and increased reactive oxygen species (ROS) production in HGFs. Genetic or pharmacologic targeting of NOX4 abrogated TGFß1-induced ROS production; Src, JNK, and Smad3 activation; and CCN2 and type I collagen protein expression in HGFs. Our results indicated that NOX4-derived ROS play pivotal roles in activating Src kinase activity leading to the activation of canonical (Smad3) and noncanonical (JNK) cascades that cooperate to attain maximum CCN2 expression. Furthermore, we demonstrated that curcumin significantly inhibited the TGFß1-induced NOX4 protein expression in HGFs. Curcumin potentially qualifies as an agent to control GO by suppressing TGFß1-induced NOX4 expression in HGFs.

FOXM1 targets NBS1 to regulate DNA damage-induced senescence and epirubicin resistance.

FOXM1 is implicated in genotoxic drug resistance but its mechanism of action remains elusive. We show here that FOXM1-depletion can sensitize breast cancer cells and mouse embryonic fibroblasts (MEFs) into entering epirubicin-induced senescence, with the loss of long-term cell proliferation ability, the accumulation of γH2AX foci, and the induction of senescence-associated ß-galactosidase activity and cell morphology. Conversely, reconstitution of FOXM1 in FOXM1-deficient MEFs alleviates the accumulation of senescence-associated γH2AX foci. We also demonstrate that FOXM1 regulates NBS1 at the transcriptional level through an forkhead response element on its promoter. Like FOXM1, NBS1 is overexpressed in the epirubicin-resistant MCF-7Epi(R) cells and its expression level is low but inducible by epirubicin in MCF-7 cells. Consistently, overexpression of FOXM1 augmented and FOXM1 depletion reduced NBS1 expression and epirubicin-induced ataxia-telangiectasia mutated (ATM)phosphorylation in breast cancer cells. Together these findings suggest that FOXM1 increases NBS1 expression and ATM phosphorylation, possibly through increasing the levels of the MRN(MRE11/RAD50/NBS1) complex. Consistent with this idea, the loss of P-ATM induction by epirubicin in the NBS1-deficient NBS1-LBI fibroblasts can be rescued by NBS1 reconstitution. Resembling FOXM1, NBS1 depletion also rendered MCF-7 and MCF-7Epi(R) cells more sensitive to epirubicin-induced cellular senescence. In agreement, the DNA repair-defective and senescence phenotypes in FOXM1-deficent cells can be effectively rescued by overexpression of NBS1. Moreover, overexpression of NBS1 and FOXM1 similarly enhanced and their depletion downregulated homologous recombination (HR) DNA repair activity. Crucially, overexpression of FOXM1 failed to augment HR activity in the background of NBS1 depletion, demonstrating that NBS1 is indispensable for the HR function of FOXM1. The physiological relevance of the regulation of NBS1 expression by FOXM1 is further underscored by the strong and significant correlation between nuclear FOXM1 and total NBS1 expression in breast cancer patient samples, further suggesting that NBS1 as a key FOXM1 target gene involved in DNA damage response, genotoxic drug resistance and DNA damage-induced senescence.

Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma.

Loss of transforming growth factor-beta receptor III (TbetaRIII) correlates with loss of transforming growth factor-beta (TGF-beta) responsiveness and suggests a role for dysregulated TGF-beta signaling in clear cell renal cell carcinoma (ccRCC) progression and metastasis. Here we identify that for all stages of ccRCC TbetaRIII expression is downregulated in patient-matched tissue samples and cell lines. We find that this loss of expression is not due to methylation of the gene and we define GATA3 as the first transcriptional factor to positively regulate TbetaRIII expression in human cells. We localize GATA3's binding to a 10-bp region of the TbetaRIII proximal promoter. We demonstrate that GATA3 mRNA is downregulated in all stages, of ccRCC, mechanistically show that GATA3 is methylated in ccRCC patient tumor tissues as well as cell lines, and that inhibiting GATA3 expression in normal renal epithelial cells downregulates TbetaRIII mRNA and protein expression. These data support a sequential model whereby loss of GATA3 expression through epigenetic silencing decreases TbetaRIII expression during ccRCC progression.

Prognostic significance of hypoxia-inducible factor-1alpha, TWIST1 and Snail expression in resectable non-small cell lung cancer.

BACKGROUND: Metastasis is the most common cause of disease failure and mortality for non-small cell lung cancer (NSCLC) after surgical resection. Snail and TWIST1 are epithelial-mesenchymal transition (EMT) regulators which induce metastasis. Intratumoral hypoxia followed by stabilisation of hypoxia-inducible factor 1alpha (HIF-1alpha) promotes metastasis through regulation of certain EMT regulators. The aim of this study was to evaluate the prognostic value of HIF-1alpha, TWIST1 and Snail expression in patients with resectable NSCLC. METHODS: A retrospective analysis of 87 patients with resectable NSCLC from Taipei Veterans General Hospital between 2003 and 2004 was performed using immunohistochemistry to analyse HIF-1alpha, TWIST1 and Snail expression. The association between HIF-1alpha, TWIST1 and Snail expression and patients' overall and recurrence-free survivals was investigated. RESULTS: Overexpression of HIF-1alpha, TWIST1 or Snail was shown in 32.2%, 36.8% and 55.2% of primary tumours, respectively. Overexpression of HIF-1alpha, TWIST1 or Snail in primary NSCLCs was associated with a shorter overall survival (p = 0.005, p = 0.026, p = 0.009, respectively), and overexpression of HIF-1alpha was associated with a shorter recurrence-free survival (p = 0.016). We categorised the patients into four groups according to the positivity of HIF-1alpha/TWIST1/Snail to investigate the accumulated effects of these markers on survival. Co-expression of more than two markers was an independent prognostic indicator for both recurrence-free survival and overall survival (p = 0.004 and p<0.001, respectively, by multivariate Cox proportional hazards model). CONCLUSIONS: Co-expression of more than two markers from HIF-1alpha, TWIST1 and Snail is a significant prognostic predictor in patients with NSCLC.

Peptides enhance magnesium signature in calcite: insights into origins of vital effects.

Studies relating the magnesium (Mg) content of calcified skeletons to temperature often report unexplained deviations from the signature expected for inorganically grown calcite. These "vital effects" are believed to have biological origins, but mechanistic bases for measured offsets remain unclear. We show that a simple hydrophilic peptide, with the same carboxyl-rich character as that of macromolecules isolated from sites of calcification, increases calcite Mg content by up to 3 mole percent. Comparisons to previous studies correlating Mg content of carbonate minerals with temperature show that the Mg enhancement due to peptides results in offsets equivalent to 7 degrees to 14 degrees C. The insights also provide a physical basis for anecdotal evidence that organic chemistry modulates the mineralization of inorganic carbonates and suggest an approach to tuning impurity levels in controlled materials synthesis.

FLJ10540-elicited cell transformation is through the activation of PI3-kinase/AKT pathway.

A significant challenge in the post-genomic era is how to prioritize differentially expressed and uncharacterized novel genes found in hepatocellular carcinoma (HCC) microarray profiling. One such category is cell cycle regulated genes that have only evolved in higher organisms but not in lower eukaryotic cells. Characterization of these genes may reveal some novel human cancer-specific abnormalities. A novel transcript, FLJ10540 was identified. FLJ10540 is overexpressed in HCC as examined by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. The patients with higher FLJ10540 expression had a poor survival than those with lower FLJ10540 expression. Functional characterization indicates that FLJ10540 displays a number of characteristics associated with an oncogene, including anchorage-independent growth, enhanced cell growth at low serum levels and induction of tumorigenesis in nude mice. FLJ10540-elicited cell transformation is mediated by activation of the phosphatidylinositol 3'-kinase (PI3K)/AKT pathway. Moreover, FLJ10540 forms a complex with PI3K and can activate PI3K activity, which provides a mechanistic basis for FLJ10540-mediated oncogenesis. Together, using a combination of bioinformatics searches and empirical data, we have identified a novel oncogene, FLJ10540, which is conserved only in higher organisms. The finding raises the possibility that FLJ10540 is a potential new therapeutic target for HCC treatment. These findings may contribute to the development of new therapeutic strategies that are able to block the PI3K/AKT pathway in cancer cells.

Overexpression of NBS1 induces epithelial-mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer.

Major causes of head and neck squamous cell carcinoma (HNSCC)-related deaths are cervical node and distant metastasis. We previously demonstrated that overexpression of the DNA double-strand break repair protein Nijmegen breakage syndrome 1 (NBS1) is a prognostic marker of advanced HNSCCs. Epithelial-mesenchymal transition (EMT) was demonstrated to be the major mechanism responsible for mediating invasiveness and metastasis of late-stage cancers. We therefore investigated the role of NBS1 overexpression in mediating EMT and metastasis. NBS1 overexpression was associated with metastasis of HNSCC patients using tissue microarray-immunohistochemistry approach. Induction of EMT was observed in an NBS1-overexpressing HNSCC cell line (FADUNBS), whereas short-interference RNA (siRNA)-mediated repression of endogenous NBS1 reversed the shift of EMT markers. Increased migration/invasiveness of FADUNBS was shown by in vitro and in vivo assays. NBS1 overexpression upregulated the expression of an EMT regulator Snail and its downstream target matrix metalloproteinase-2. EMT phenotypes and increased migration/invasiveness of FADUNBS cells were reversed by siRNA-mediated repression of Snail expression or a phosphatidylinositol 3-kinase-specific inhibitor. In HNSCC samples, co-expression of NBS1/Snail in primary tumors correlated with metastasis and the worst prognosis. These results indicate that NBS1 overexpression induces EMT through the upregulation of Snail expression, and co-expression of NBS1/Snail predicts metastasis in HNSCCs.

Inclusion cyst and graft contraction in Tutoplast human cadeveric pericardium following Peyronie's grafting: a previously unreported complication.

Tutoplast human cadaveric pericardium has been utilized safely and successfully in numerous series of tunica albuginea grafting for Peyronie's curvature without reported rejection, cyst formation, or foreign body reaction. We describe a previously unreported complication of inclusion cyst formation and graft contraction in a 40-year-old white male following Tutoplast human cadaveric pericardial graft surgical correction of Peyronie's curvature. The complication was successfully treated with surgical graft excision and replacement with autologous temporalis fascia.

Characterization of differential gene expression in monkey arterial neointima following balloon catheter injury.

Vaso-occlusive sequelae following percutaneous transluminal coronary angioplasty (PTCA), including smooth muscle cell migration, proliferation, and attendant extracellular matrix production, often results in restenosis of the treated artery. To further understand the molecular mechanisms governing progressive intimal hyperplasia, we performed a molecular screen using differential display PCR on total RNA prepared from injured and normal carotid arterial segments to identify a subset of differentially expressed genes at t=7 days post-balloon catheter injury in a non-human primate. DNA sequence analysis of selected differentially expressed RNA by this procedure using 240 combinations of random primer pairs yielded 41 distinct cDNA sequences: 22 of which have significant sequence homology to previously identified meta-zoan genes, 15 GEMS (genes expressed in monkey neointima), and 4 GSMS (genes suppressed in monkey neointima) that have little homology to reported sequences. Among the up-regulated homologues include i) secreted growth regulatory factors, ii) membrane receptors, iii) transcription factors, iv) cell adhesion molecules, and v) extracellular matrix proteins; some of which have not been previously linked to vascular restenosis. In particular, Cyr61, a known angiogenesis inducer, was found to be highly expressed in the neointima lesion of the balloon-injured monkey artery. This finding provides the first links of Cyr61 to the pathogenesis of vascular restenosis, and identifies a novel locus for potential therapeutic intervention. These studies identified a number of known and unknown genes, whose up- or down-regulated expression during the proliferative phase of vascular restenosis makes them potential targets for therapeutic intervention.

Activation of p53 tumor suppressor by hepatitis C virus core protein.

In addition to being a structural protein that packages the viral genomic RNA, hepatitis C virus (HCV) core protein possesses regulatory functions. In this report, we demonstrate that the HCV core protein could enhance the gene transactivation activity of the tumor suppressor p53, regardless of whether p53 was derived from an exogenous or an endogenous gene. The activation of p53 by the HCV core protein was supported by the observation that the HCV core protein could enhance the expression of p21(waf1/Cip1), a downstream effector gene of p53, in a p53-dependent manner. Further studies indicated that the HCV core protein could also suppress hepatocellular growth via p53. The HCV core protein and p53 could bind to each other in vitro, which was evidenced by the coimmunoprecipitation, the GST pull-down, and the Far-Western blot assays. The deletion-mapping analysis indicated that the carboxy-terminal sequence of p53 located between amino acids 366 and 380 was required for the core protein binding. These results raised the possibility that the HCV core protein might activate p53 through direct physical interaction. The persistent perturbation of p53 activity by the HCV core protein during chronic infection may have important consequences in HCV pathogenesis.

Discovery of a regulatory motif that controls the exposure of specific upstream cyclin-dependent kinase sites that determine both conformation and growth suppressing activity of pRb.

The conformation and activity of pRb, the product of the retinoblastoma susceptibility gene, is dependent on the phosphorylation status of one or more of its 16 potential cyclin-dependent kinase (cdk) sites. However, it is not clear whether the phosphorylation status of one or more of these sites contributes to the determination of the various conformations and activity of pRb. Moreover, whether and how the conformation of pRb may regulate the phosphorylation of the cdk sites is also unclear. In the process of analyzing the function and regulation of pRb, we uncovered the existence of an unusual structural motif, m89 (amino acids 880-900), the mutation of which confers upon pRb a hypophosphorylated conformation. Mutation of this structural domain activates, rather than inactivates, the growth suppressor function of pRb. In order to understand the effect of the mutation of m89 on the phosphorylation of cdk sites, we identified all the cdk sites (Thr-356, Ser-807/Ser-811, and Thr821) the phosphorylation of which drastically modify the conformation of pRb. Mutation of each of these four sites alone or in combinations results in the different conformations of pRb, the migration pattern of which, on SDS-polyacrylamide gel electrophoresis, resembles various in vivo hypophosphorylated forms. Each of these hypophosphorylated forms of pRb has enhanced growth suppressing activity relative to the wild type. Our data revealed that the m89 structural motif controls the exposure of the cdk sites Ser-807/Ser-811 in vitro and in vivo. Moreover, the m89 mutant has enhanced growth suppressing activity, similar to a mutant with alanine substitutions at Ser-807/Ser-811. Our recent finding, that the m89 region is part of a structural domain, p5, conserved antigenically and functionally between pRb and p53, suggests that the evolutionarily conserved p5 domain may play a role in the coordinated regulation of the activity of these two tumor suppressors, under certain growth conditions.

Direct activation of TERT transcription by c-MYC.

The MYC proto-oncogene encodes a ubiquitous transcription factor (c-MYC) involved in the control of cell proliferation and differentiation. Deregulated expression of c-MYC caused by gene amplification, retroviral insertion, or chromosomal translocation is associated with tumorigenesis. The function of c-MYC and its role in tumorigenesis are poorly understood because few c-MYC targets have been identified. Here we show that c-MYC has a direct role in induction of the activity of telomerase, the ribonucleoprotein complex expressed in proliferating and transformed cells, in which it preserves chromosome integrity by maintaining telomere length. c-MYC activates telomerase by inducing expression of its catalytic subunit, telomerase reverse transcriptase (TERT). Telomerase complex activity is dependent on TERT, a specialized type of reverse transcriptase. TERT and c-MYC are expressed in normal and transformed proliferating cells, downregulated in quiescent and terminally differentiated cells, and can both induce immortalization when constitutively expressed in transfected cells. Consistent with the recently reported association between MYC overexpression and induction of telomerase activity, we find here that the TERT promoter contains numerous c-MYC-binding sites that mediate TERT transcriptional activation. c-MYC-induced TERT expression is rapid and independent of cell proliferation and additional protein synthesis, consistent with direct transcriptional activation of TERT. Our results indicate that TERT is a target of c-MYC activity and identify a pathway linking cell proliferation and chromosome integrity in normal and neoplastic cells.

Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC.

The protein encoded by the c-MYC proto-oncogene is a transcription factor that can both activate and repress the expression of target genes, but few of its transcriptional targets have been identified. Here, c-MYC is shown to repress the expression of the heavy subunit of the protein ferritin (H-ferritin), which sequesters intracellular iron, and to stimulate the expression of the iron regulatory protein-2 (IRP2), which increases the intracellular iron pool. Down-regulation of the expression of H-ferritin gene was required for cell transformation by c-MYC. These results indicate that c-MYC coordinately regulates genes controlling intracellular iron concentrations and that this function is essential for the control of cell proliferation and transformation by c-MYC.