Negotiating Gestational Diabetes Mellitus in India: A National Approach.

The worldwide epidemic of diabetes mellitus and hyperglycemia in pregnancy (HIP) presents many challenges, some of which are country-specific. To address these specific problems, parochial resolutions are essential. In India, the government, by working in tandem with (a) national groups such as the Diabetes in Pregnancy Study Group of India, and (b) global organizations such as the International Diabetes Federation, has empowered the medical and paramedical staff throughout the country to manage HIP. Additionally, despite their academic university backgrounds, Indian health planners have provided practical guidelines for caregivers at the ground level, who look up to these experts for guidance. This multipronged process has helped to negotiate some of the multiple problems that are indigenous and exclusive to India. This review traces the Indian journey to manage and prevent HIP with simple, constructive, and pragmatic solutions.

A survey of retaining faculty at a new medical school: opportunities, challenges and solutions.

BACKGROUND: At well-established academic university settings, retaining faculty remains a pressing challenge due to competing market forces, decreasing institutional support, and changing personal expectations. There is a paucity of information about the difficulties faced by new medical schools to maintain their academic workforce. The objective of this study was to determine the challenges facing the faculty at a newly developed medical school. METHODS: Twelve founding faculty were surveyed anonymously by a 32-item questionnaire. Their responses were independently analyzed by three researchers. RESULTS: The views of the faculty were categorized into in four inter-related themes: personal, support, institutional, and environmental. The constant sources of satisfaction among faculty were higher academic rank (75%), harmonious inter-collegial relationships (74%), healthy pecuniary rewards (58%), better professional growth (58%) along with greater autonomy, administrative independence, minimum groupism and excellent team work. Poor opportunities for promotion (68%), reduced support for scholarly activities (67%) and unsatisfactory support from the administration (55%) were detrimental to retaining faculty. CONCLUSION: By addressing specific issues facing its staff, every new medical school will not only manage to retain its academic faculty but also be able to attract well qualified academic staff from established medical institutions worldwide.

Curriculum mapping as a tool to facilitate curriculum development: a new School of Medicine experience.

BACKGROUND: Every curriculum needs to be reviewed, implemented and evaluated; it must also comply with the regulatory standards. This report demonstrates the value of curriculum mapping (CM), which shows the spatial relationships of a curriculum, in developing and managing an integrated medical curriculum. METHODS: A new medical school developed a clinical presentation driven integrated curriculum that incorporates the active-learning pedagogical practices of many educational institutions worldwide while adhering to the mandated requirements of the accreditation bodies. A centralized CM process was run in parallel as the curriculum was being developed. A searchable database, created after the CM data was uploaded into an electronic curriculum management system, was used to ensure placing, integrating, evaluating and revising the curricular content appropriately. RESULTS: CM facilitated in a) appraising the content integration, b) identifying gaps and redundancies, c) linking learning outcomes across all educational levels (i.e. session to course to program), c) organizing the teaching schedules, instruction methods, and assessment tools and d) documenting compliance with accreditation standards. CONCLUSIONS: CM is an essential tool to develop, review, improve and refine any integrated curriculum however complex. Our experience, with appropriate modifications, should help other medical schools efficiently manage their curricula and fulfill the accreditation requirements at the same time.

Breast cancer protection by genomic imprinting in close kin families.

Human inbreeding generally reduces breast cancer risk (BCR). When the parents are biologically related, their infants have a lower birth weight due to smaller body organs. The undersized breasts, because of fewer mammary stem cells, have a lower likelihood of malignant conversion. Fetal growth is regulated by genomically imprinted genes which are in conflict; they promote growth when derived from the father and suppress growth when derived from the mother. The kinship theory explicates that the intensity of conflict between these genes affects growth and therefore the size of the newborn. In descendants of closely related parents, this gene clash is less resulting in a smaller infant. In this review, we elucidate the different mechanisms by which human inbreeding affects BCR, and why this risk is dissimilar in different inbred populations.

Analysis of the pH-dependent stability and millisecond folding kinetics of horse cytochrome c.

This paper analyzes the effect of pH on thermodynamic stability and folding kinetics of horse cytochrome c (cyt c). Analysis of equilibrium unfolding transitions of Ferricyt c and Ferrocyt c measured between pH 3.0 and pH 13.0 reveal that these proteins have maximum thermodynamic stability between pH 8.0 and pH 9.5. Theoretically predicted pH-dependent electrostatic unfolding energy of Ferricyt c also supports this result. Unfolded Ferrocyt c in refolding buffer at pH 7.0 and pH 12.7 refolds rapidly to native state. Between pH 7.0 and pH 12.7, the activation free energy barrier for folding of Ferrocyt c varies by <1.0 kcal mol(-1) while the folding free energy, which is measured by two-state analysis of equilibrium unfolding transitions of Ferrocyt c varies by 8.0 kcal mol(-1). This finding reveals that the large disparity in thermodynamic stability between pH 7.0 and pH 12.7 is not strongly reflected in the refolding rates. The Wyman Tanford linkage relation was used to calculate the ß(pH)-value for folding of Ferrocyt c, which is <0.1 between pH 7.0 and pH 12.7, indicating that the electrostatic interactions are weakly formed in transition state and exhibit a very small effect on the folding kinetics.

Association between acculturation, obesity and cardiovascular risk factors among male South Asian migrants in the United Arab Emirates--a cross-sectional study.

BACKGROUND: Approximately 65% of the United Arab Emirates (UAE) population are economic migrants from the low- and middle-income countries of South Asia. Emerging evidence suggests that expatriate populations from low or middle-income countries that migrate to high-income countries acculturate their lifestyle with the obesogenic behaviours of the host country. Previous research has focussed on migrant populations in the United States. The objective of this study was to assess the prevalence of obesity and explore the relationship between years of residency (surrogate measure for acculturation) and obesity among South Asian (from India, Pakistan and Bangladesh) male immigrants residing in the UAE. METHODS: A random sample of 1375 males was recruited from a mandatory residency visa health screening centre in Abu Dhabi (UAE). Employing a cross-sectional design, participants completed an interviewer-led adapted version of the World Health Organisation STEPS questionnaire, and anthropometric and blood pressure measurements were collected. Glycated haemoglobin (HbA1c) was measured in a random sub-sample (n = 100). Logistic regression was used to determine risk factors for being classified as obese, and to assess the relationship between years of residency and adiposity. RESULTS: The overall prevalence of body mass index-derived overweight and obesity estimates and waist-to-hip-derived central obesity rates was 615 (44.7%) and 917 (66.7%) males, respectively. Hypertension was present in 419 (30.5%) of the sample and diabetes in 9 (9.0%) of the sub-sample. Living in the UAE for six to 10 years or more than 10 years was independently associated with being classified with central obesity (adjusted odds ratio [AOR] 1.63 95% confidence intervals [CI] 1.13 - 2.35, p < 0.008; AOR 1.95 95% CI 1.26 - 3.01, p < 0.002; respectively) compared to residing in the UAE for one to five years. CONCLUSIONS: Our study revealed a high prevalence of overweight, central obesity and hypertension amongst a young South Asian male migrant population in the UAE. Study findings suggest a diminished 'Healthy Migrant Effect' with increased years of residency possibly due to greater acculturation and a transition in lifestyle behaviours. Health initiatives targeting the maintenance of a healthy body size, coupled with regular assessments of glucose control and blood pressure are urgently required in this population.

Gestational diabetes mellitus: Confusion among medical doctors caused by multiple international criteria.

AIM: The aim of this study was to appraise the current regional practices of screening, diagnosis and follow-up of gestational diabetes mellitus (GDM) because the approach to GDM is frequently inconsistent. MATERIAL AND METHODS: A 21-item questionnaire was distributed to physicians taking care of pregnant women in seven hospitals in the United Arab Emirates and one hospital in Oman. Besides assessing their attitudes towards testing for GDM, the questionnaire assessed familiarity with the Hyperglycemia and Pregnancy Outcome study and the International Association of Diabetes in Pregnancy Study Groups GDM guidelines. RESULTS: One hundred and forty-eight (93%) of the 159 questionnaires distributed to the medical doctors (106 [72%] obstetricians and 42 [28%] internists) were returned. For GDM screening, six hospitals used five different tests; two hospitals utilized one single test. For GDM diagnosis, six hospitals employed the 2-h, 75-g oral glucose tolerance test (OGTT) (four different criteria) while two hospitals used the 3-h, 100-g OGTT (single criteria). For post-delivery follow-up, the 2-h, 75-g OGTT and fasting plasma glucose were accepted by 103 (70%) and 38 (26%) of the 148 medical doctors, respectively. Ninety-eight (69%) of 143 responding physicians were aware of the Hyperglycemia and Pregnancy Outcome study, while 85 (61%) of 140 responders were familiar with the guidelines of the International Association of Diabetes in Pregnancy Study Groups; this knowledge was independent of specialty, seniority, academia, years in practice or country trained. CONCLUSIONS: Although this study is parochial, its implications are global; that is, further education of caregivers would make the discordant approach to GDM (within and between hospitals) more harmonious and improve the obstetric care of pregnant women.

Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers.

Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1 (refs 3, 4), led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy.

Identifying Populations at Risk for Lung Cancer Mortality from the National Health and Nutrition Examination Survey (2001-2018) Using the 2021 USPSTF Screening Guidelines.

Lung cancer (LC) is the leading cause of cancer mortality in the United States. To combat this predicament, early screening and critically assessing its risk factors remain crucial. The aim of this study was to identify the value of specific factors from the National Health and Nutrition Examination Survey (NHANES) from 2001-2018, as they relate to lung cancer mortality in the US Preventive Services Task Force (USPSTF)-eligible population. A total of 3545 adults who met USPSTF criteria were extracted from 81,595 NHANES participants. The LC Death Risk Assessment Tool was used to calculate the number of deaths per 1000 individuals. The Mann-Whitney U test and one-way ANOVA determined the statistical significance of the factors involved in LC mortality. Male sex, African and Hispanic ethnicity, lower education attainment, and secondhand exposure to cigarette smoke correlated with an increased risk of LC mortality. Additionally, the factor of emotional support from NHANES data was analyzed and did not show any benefit to reducing risk. By identifying individuals at high-risk, preventative measures can be maximized to produce the best possible outcome.

ATP depletion triggers acute myeloid leukemia differentiation through an ATR/Chk1 protein-dependent and p53 protein-independent pathway.

Despite advances in oncology drug development, most commonly used cancer therapeutics exhibit serious adverse effects. Often the toxicities of chemotherapeutics are due to the induction of significant DNA damage that is necessary for their ability to kill cancer cells. In some clinical situations, the direct induction of significant cytotoxicity is not a requirement to meet clinical goals. For example, differentiation, growth arrest, and/or senescence is a valuable outcome in some cases. In fact, in the case of acute myeloid leukemia (AML), the use of the differentiation agent all-trans-retinoic acid (ATRA) has revolutionized the therapy for a subset of leukemia patients and led to a dramatic survival improvement. Remarkably, this therapeutic approach is possible even in many elderly patients, who would not be able to tolerate therapy with traditional cytotoxic chemotherapy. Because of the success of ATRA, there is widespread interest in identifying differentiation strategies that may be effective for the 90-95% of AML patients who do not clinically respond to ATRA. Utilizing an AML differentiation agent that is in development, we found that AML differentiation can be induced through ATP depletion and the subsequent activation of DNA damage signaling through an ATR/Chk1-dependent and p53-independent pathway. This study not only reveals mechanisms of AML differentiation but also suggests that further investigation is warranted to investigate the potential clinical use of low dose chemotherapeutics to induce differentiation instead of cytotoxicity. This therapeutic approach may be of particular benefit to patients, such as elderly AML patients, who often cannot tolerate traditional AML chemotherapy.

Gestational diabetes in a tertiary care hospital: implications of applying the IADPSG criteria.

BACKGROUND: The American Diabetes Association has endorsed the International Association of Diabetes and Pregnancy Groups (IADPSG) recommendation that every pregnant woman should undergo the 75 g oral glucose tolerance test (OGTT) to screen for gestational diabetes mellitus (GDM). PURPOSE: To find the cost and workload implications of switching from the current two-step screening of GDM to the one-step IADPSG approach. METHODS: The cost (US $) and laboratory workload units (WLU) were calculated for three possible strategies: (1) 50 g glucose screen, if positive, followed by the 100 g OGTT; (2) universal 75 g OGTT; and (3) screening with the initial fasting plasma glucose of the OGTT. RESULTS: For the 1,101 pregnant women screened in 1 year, the cost of the three strategies was $ 31,985, $ 55,250 and $ 35,875, respectively; the laboratory burden was 28,975 WLU, 18,662 WLU and 12,215 WLU, respectively. CONCLUSIONS: Switching to the one-step, strategy 2 (IADPSG) would increase the cost by 42 % but decrease the laboratory workload by 36 % compared to the two-step, strategy 1. However, an initial screen by the fasting plasma glucose of the OGTT is the ideal strategy, both in terms of cost and laboratory workload.

Gestational Diabetes Mellitus in a Multi-Ethnic, High-Risk Population: Adequacy of Screening for Diabetes Mellitus 6 Weeks after Delivery.

Gestational diabetes mellitus (GDM) during pregnancy is a marker for future type 2 diabetes mellitus (T2DM); therefore, a meticulous follow-up after delivery can help identify women at risk for T2DM. In a cohort of 5504 pregnant women, the postpartum follow-up of all 1043 women with GDM for hyperglycemia in a multi-ethnic, high-risk Arab population was investigated. The prevalence of GDM was 18.9%. A total of 265 (25.4%) women returned for an oral glucose tolerance test (OGTT) 4-6 weeks after delivery, with more South Asian than Arab women (p < 0.01). The other factors associated with return were (a) family history of T2DM, (b) lower basic metabolic index, (c) higher abortions and (d) lower gravida (p < 0.05), all with minimal effect. An abnormal postpartum OGTT was statistically associated with previous GDM history and hypoglycemic drug treatment, although these effects were small. Overall, the follow-up of women with GDM postpartum was dismal, ethnicity being the major factor influencing return. Urgent public measures are needed to educate women with GDM about follow-up highlighting (a) risk awareness for T2DM and (b) a healthy lifestyle after childbirth-if we are to turn the tide on the epidemic of T2DM plaguing the Arab world.

Securinine induces p73-dependent apoptosis preferentially in p53-deficient colon cancer cells.

The identification of agents that preferentially kill cancer cells while protecting normal cells offers the potential to overcome toxicities found in many existing chemotherapeutic agents. Because p53 is frequently inactivated in cancer, agents that preferentially kill p53-null cells and protect wild-type p53-expressing cells are highly desirable chemotherapeutic agents. By using pairs of isogenic colon cancer cell lines that differ only in p53 expression (RKO and HCT116), securinine was found to exhibit these properties. Securinine (30 microM) induces apoptosis in 73% of p53-null HCT116 cells (LD(50) 17.5 microM) as opposed to 17.6% of HCT116 parental cells (LD(50) 50 microM) at 72 h after treatment. The mechanism of securinine-mediated death in p53-deficient cells involves the induction of the p53 family member, p73. Interestingly, the proapoptotic protein p73 is down-regulated in colon cancer cells expressing p53. This differential regulation of p73 in a p53-dependent fashion reveals a novel pathway for preferentially targeting cancer cells. In contrast to p53-deficient cells, cells expressing p53 are protected from cell death through the p53-mediated up-regulation of p21. These studies reveal a novel approach to specifically target colon cancer cells lacking p53 as well as identify a novel clinically relevant pathway to selectively induce p73 in p53-null cells.

DNA synthesis from unbalanced nucleotide pools causes limited DNA damage that triggers ATR-CHK1-dependent p53 activation.

p53-dependent G(1) and G(2) cell cycle checkpoints are activated in response DNA damage that help to maintain genomic stability. p53 also helps to protect cells from damage that occurs during S phase, for example, when the cells are starved for DNA precursors or irradiated with a low dose of UV. p53 is activated in normal cells starved for pyrimidine nucleotides by treatment with N-(phosphonacetyl)-l-aspartate (PALA). The treated cells progress through a first S phase with kinetics similar to those of untreated cells. However, the DNA of the treated cells begins to become damaged rapidly, within 12 h, as revealed by a comet assay, which detects broken DNA, and by staining for phosphorylated histone H2AX, which accumulates at sites of DNA damage. Because the cells survive, the damage must be reversible, suggesting single-strand breaks or gaps as the most likely possibility. The transiently damaged DNA stimulates activation of ATR and CHK1, which in turn catalyze the phosphorylation and accumulation of p53. Although PALA-induced DNA damage occurs only in dividing cells, the p53 that is activated is only competent to transcribe genes such as p21 and macrophage inhibitory cytokine 1 (whose products regulate G(2) and G(1) or S phase checkpoints, respectively) after the cells have exited the S phase during which damage occurs. We propose that p53 is activated by stimulation of mismatch repair in response to the misincorporation of deoxynucleotides into newly synthesized DNA, long before the lack of pyrimidine nucleoside triphosphates causes the rate of DNA synthesis to slow appreciably.

Gestational diabetes: an evaluation of serum fructosamine as a screening test in a high-risk population.

AIM: To evaluate the value of serum fructosamine as a screening test for gestational diabetes mellitus (GDM). METHODS: 849 pregnant women underwent the one-step 75 g oral glucose tolerance test (OGTT) for universal screening of GDM. The fasting serum fructosamine (cFruc) was assessed using the area under the receiver operating characteristic curve (AUC). The GDM diagnostic criteria used were those of the American Diabetes Association; however, the cFruc performance was also evaluated using criteria of the World Health Organization, Australian (ADIPS), European (EASD) and International Association of Diabetes and Pregnancy Study Groups (IADPSG). RESULTS: 113 (13.3%) women had GDM. The AUC of the cFruc was 0.60 (95% CI 0.54-0.66). A cFruc threshold of 237 µmol/l achieved an acceptable sensitivity of 85.8% (95% CI 78.0-91.0%), but the associated specificity remained poor at 23.4% (95% CI 20.0-27.0%) with a positive predictive value of just 14.7%. Overall, over 4 out of 5 pregnant women, being over this cutoff, would need the confirmatory OGTT. No cFruc threshold reached acceptable likelihood ratios to rule-in or rule-out GDM. The AUC for cFruc remained unacceptable independent of the diagnostic criteria. CONCLUSIONS: Despite all the advances in technology, serum fructosamine is a poor test to screen for GDM.

Altruism as an Explanation for Human Consanguinity.

BACKGROUND: Human inbreeding is a sociobiological puzzle. Despite widespread knowledge of its potential for genetic disorders, human consanguinity remains surprisingly common. The current reasons explaining its continued persistence in today's modern world have major shortcomings. SUMMARY: We propose that the Neolithic Agrarian revolution modified the structure of populations. It increased competition for the limited resources in which a larger group had better chances of survival. As a result, small, drifting, socially open bands of hunter-gatherers were transformed into bigger, less mobile, and more powerful kinship groups (tribes). In this transformation, a central role was played by human trust - an aspect of human altruism which is a universal sociobiological principle of behavior. Altruism (and trust) is an essential premise of social contracts such as economic cooperation, marriage arrangement, and creation of alliances between people. In kinship groups, human trust is limited to kin, so tribes remain small, economically poor, and consanguineous due to lack of nonkin mates. The expanding of trust from kin to that of nonbiological relatives increases the size of human groups, fosters economic wealth, and decreases the rate of consanguinity. Key Messages: The lack of nonkin altruism leads to: (a) poverty (due to poor economic cooperation with nonkin), (b) maintaining small group size, and (c) inbreeding.

Choice of kin in consanguineous marriages: effects of altruism and ecological factors.

BACKGROUND: Despite being associated with multiple genetic problems, consanguineous marriages continue to remain extremely prevalent worldwide. Studying the variation of kin preferences in diverse inbred societies may provide some answers to this paradox. AIM: To find the reasons for specific kin choice in different geographical areas of the world. METHOD: We used a set of sociobiological rules (kin altruism, sexuality and inbreeding avoidance) and ecological constraints (e.g. tribal warfare, food availability) that influence human behaviour. The cumulative help that the extended family can provide to a nuclear family was calculated using the coefficient of relatedness between kin in different types of consanguineous families. RESULTS: The maximum potential support for kin markedly varied between different types of consanguineous marriages. Overall, members of consanguineous families received up to two-and-half times more support than members of non-consanguineous families. In various inbred cultures, preference for a specific type of kin was determined by prevailing ecological limitations and sociobiological factors interacting in a complex manner. CONCLUSION: In different inbred populations, the ideal kin for a consanguineous marriage is the one who can provide the most altruistic support; however, this choice is influenced by biological rules of behaviour and ecological constraints.

Gestational Diabetes in the Arab Gulf Countries: Sitting on a Land-Mine.

Type 2 diabetes mellitus (T2DM) has become a modern-day plague by reaching epidemic levels throughout the world. Due to its similar pathogenesis, gestational diabetes (GDM) increases in parallel to T2DM. The prevalence of T2DM (3.9-18.3%) and GDM (5.1-37.7%) in countries of the Arab Gulf are amongst the highest internationally, and they are still rising precipitously. This review traces the reasons among the Arab nations for (a) the surge of T2DM and GDM and (b) the failure to contain it. During the last five decades, the massive oil wealth in many Arab countries has led to the unhealthy lifestyle changes in physical activity and diet. The excess consumption of calories turned the advantageous genes, originally selected for the famine-like conditions, detrimental: fueling obesity and insulin resistance. Despite genetic differences in these populations, GDM-a marker for future obesity and T2DM-can overcome this scourge of T2DM through active follow-up and screening after delivery. However, the health policies of most Arab countries have fallen short. Neglecting this unique chance will miss an irreplaceable opportunity to turn the tide of the T2DM and obesity epidemic in the Middle Eastern Arab Gulf countries-as well as globally.

Prevalence, phenotype and inheritance of benign neutropenia in Arabs.

BACKGROUND: Benign neutropenia, i.e., neutropenia not associated with an increased risk of infection, may result in serious medical consequences when a 'standard' definition of neutropenia (absolute neutrophil count (ANC) < 1.5 x 10(9)cells/L) is universally applied to all races. The aims of this study were to determine the prevalence of benign neutropenia among healthy Arabs and evaluate its mode of inheritance. METHODS: ANCs were studied prospectively amongst a healthy indigenous population (n = 1032) from the United Arab Emirates undergoing a nation-wide sickle-cell and thalassemia screening program. The mean neutrophil count and the prevalence of benign neutropenia were compared by age, sex and amongst various tribes. RESULTS: The mean neutrophil count (x 10(9)cells/L) was 3.3 (range 0.95-7.6). Benign neutropenia was present in 110 (10.7%) subjects of whom 24 (2.3%) individuals had moderate neutropenia (ANC 0.5 - 1.0 x 10(9) cells/L). In the 22 tribe-family groups, the prevalence of benign neutropenia varied between 0% and 38%. Benign neutropenia showed no difference in the frequency amongst the sexes (p = 0.23) and it was independent of age (Spearman's rho = 0.05, p = 0.13). The age-related mean neutrophil count was the lowest in Arabs when compared with other ethnic groups (Blacks, Europeans and Mexicans). The inheritance of benign neutropenia was consistent with an autosomal dominant pattern; however, the diversity of observed phenotypes suggested the presence of more than one genetic variant for this trait. CONCLUSION: Arabs have a high prevalence of benign neutropenia that may be inherited as an autosomal dominant trait.

DNA replication licensing factor minichromosome maintenance deficient 5 rescues p53-mediated growth arrest.

Inactivation of p53 signaling by mutation of p53 itself or abrogation of its normal function by other transfactors, such as MDM2, is a key event in the development of most human cancers. To identify novel regulators of p53, we have used a phenotype-based selection in which a total cDNA library in a retroviral vector has been introduced into TR9-7ER cells, which arrest when p53 is expressed from a tetracycline-regulated promoter. We have isolated several clones derived from cells that are not growth-arrested when p53 is overexpressed. In one clone, the levels of p53, p21, and MDM2 are comparable with those in TR9-7ER cells and, therefore, the abrogation of growth arrest by an exogenous cDNA is likely to be distal to p21. Using reverse transcription-PCR, we were able to isolate a cDNA of approximately 2.2 kb, which was found to have 99% identity to the nucleotides between about 80 and 2,288 of the open reading frame of a gene encoding DNA replication licensing factor. It encodes complete peptide of 734 residues of this protein also called minichromosome maintenance deficient 5 (MCM5) or cell division cycle 46 (Saccharomyces cerevisiae). Northern and Western blot analyses revealed that the expression of MCM5 and its transcriptional regulator, E2F1, is negatively regulated by p53. When MCM5 cDNA was reintroduced into fresh TR9-7ER cells, numerous colonies that grow in the absence of tetracycline were formed. This novel observation establishes a role for MCM5 in negating the growth arrest function of p53.