Contributions of the Community-Based Organization Program Funded by the Centers for Disease Control and Prevention to Linkage to HIV Medical Care.

OBJECTIVE: Linkage to HIV medical care is important in the continuum of HIV care and health outcomes for people with HIV. The objective of this analysis was to identify how the community-based organization (CBO) program contributes to linkage to HIV medical care among people with newly diagnosed HIV in the Centers for Disease Control and Prevention's (CDC's) HIV testing program. METHODS: We analyzed HIV linkage-to-care data submitted to CDC from 2019 through 2021. Linkage was defined as confirmation that an individual attended their first HIV medical care appointment within 30 days of their HIV test date. We included in the analysis data submitted from the health department (HD) program that included 61 state and local HDs in the United States, Puerto Rico, and the US Virgin Islands and the CBO program that included 150 CBOs. RESULTS: The CBO program linked a higher proportion of people to HIV medical care within 30 days of diagnosis (86.7%) than the HD program (73.7%). By population group, the proportion linked in the CBO program was higher than the proportion linked in the HD program among men who have sex with men (prevalence ratio [PR] = 1.13; P < .001), men who have sex with men/people who inject drugs (PR = 1.29; P < .001), transgender people (PR = 1.28; P < .001), and those reporting no sexual contact or injection drug use (PR = 1.34; P < .001). In the Cox proportional hazards model, time to linkage in the CBO program was significantly shorter than in the HD program (hazard ratio = 0.63; P < .001). CONCLUSION: This analysis shows that the CBO program fills a vital need in linking newly diagnosed HIV-positive people to HIV medical care, which is important in the HIV care continuum and for viral suppression.

Asian People Reached by the Centers for Disease Control and Prevention HIV Testing Program in the United States: HIV Testing, Linkage to HIV Medical Care, and Interview for Partner Services 2014-2020.

The purpose of this analysis is to describe HIV tests and associated outcomes for Asian people reached by the Centers for Disease Control and Prevention (CDC) HIV testing program. We analyzed CDC-funded HIV tests among Asian individuals in the United States, Puerto Rico, and the U.S. Virgin Islands (2014-2020). Of the 415,560 tests, the positivity of new diagnoses was higher among males (0.49%, aPR = 7.64) than females (0.06%), and in the West (0.42%, aPR = 1.15) than in the South (0.25%). In non-health care settings, positivity was highest among men who have sex with men (MSM; 0.87%) and transgender people (0.46%). Linkage to HIV medical care among Asian people was 87.5%, and 70.7% were interviewed for partner services. Our findings suggest that improvements are crucial, particularly for Asian MSM, in linkage to care and interview for partner services.

CDC-Funded HIV Testing and Linkage to HIV Medical Care Among American Indian and Alaska Native People in the United States, 2014-2020.

OBJECTIVE: An estimated 1 in 5 American Indian and Alaska Native (AI/AN) adults living with HIV are unaware of their status. We investigated HIV testing among AI/AN people receiving a Centers for Disease Control and Prevention (CDC)-funded test from 2014 through 2020. METHODS: We analyzed data on CDC-funded HIV tests reported by health departments and community-based organizations in the United States. We described the number of CDC-funded HIV tests, the percentage of people with newly and previously diagnosed HIV, and linkage to HIV medical care within 90 days of diagnosis. RESULTS: CDC-funded health departments and community-based organizations provided 99 227 HIV tests to AI/AN people during 2014-2020. Seven hundred thirty-five (0.7%) AI/AN people were diagnosed with HIV; 361 (0.4%) were newly diagnosed, 319 (0.3%) had a previous HIV diagnosis, and 55 (0.1%) had a previously unknown HIV status. Positivity for new diagnoses was highest among the following population groups tested in non-health care settings: men who had sex with men (MSM; n = 72, 1.2%), MSM who inject drugs (n = 12, 1.8%), and transgender people (n = 12, 1.5%). The percentage of linkage to HIV medical care was 80.6% for newly diagnosed people and 78.2% for previously diagnosed people. CONCLUSIONS: MSM AI/AN, including those who inject drugs, and transgender AI/AN may benefit from prioritized HIV testing. All AI/AN people with HIV, whether newly or previously diagnosed, should rapidly link to HIV medical care and receive support throughout the continuum of care. Our findings can inform which AI/AN population subgroups may benefit from enhanced HIV testing efforts and interventions.

Contributions of Community-Based Organizations Funded by the Centers for Disease Control and Prevention's HIV Testing Program.

CONTEXT: HIV testing is a critically important first step in preventing and reducing HIV transmission. Community-based organizations (CBOs) are uniquely positioned to provide HIV testing and other prevention services to populations disproportionately affected by HIV infection. OBJECTIVE: The purpose of this analysis was to assess CDC-funded health department (HD) and CBO testing programs during 2012-2017, including the number of tests and HIV positivity. DESIGN: This is an analysis of National HIV Prevention Program Monitoring and Evaluation HIV testing data submitted between 2012 and 2017 to CDC. SETTING: Sixty-one CDC-funded state and local HDs in the United States, Puerto Rico, and the US Virgin Islands and between 122 and 175 CDC-funded CBOs, depending on the year. PARTICIPANTS: Persons who received HIV testing at CDC-funded CBOs and HDs. MAIN OUTCOME MEASURE: The number of HIV tests and positivity at CBOs were compared with HDs overall and to HDs in non-health care settings that, like CBOs, include HIV risk data and are in similar locations. RESULTS: CBOs accounted for 7625 (8%) new diagnoses but conducted only 3% of the almost 19 million CDC-funded HIV tests from 2012 to 2017. Newly diagnosed HIV positivity at CBOs (1.4%) was nearly 3 times the new positivity at HDs overall (0.5%) and twice that of new positivity at HDs in non-health care settings (0.7%). A higher proportion of tests at CBOs were conducted among groups at risk, and new HIV positivity was higher for most demographic and population groups than new HIV positivity at HDs in non-health care settings. CONCLUSION: These findings demonstrate the essential role CDC-funded CBOs have in reaching, testing, and diagnosing groups at high risk for acquiring HIV infection.

Demographic, clinical, and epidemiologic characteristics of persons under investigation for Coronavirus Disease 2019-United States, January 17-February 29, 2020.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), evolved rapidly in the United States. This report describes the demographic, clinical, and epidemiologic characteristics of 544 U.S. persons under investigation (PUI) for COVID-19 with complete SARS-CoV-2 testing in the beginning stages of the pandemic from January 17 through February 29, 2020. METHODS: In this surveillance cohort, the U.S. Centers for Disease Control and Prevention (CDC) provided consultation to public health and healthcare professionals to identify PUI for SARS-CoV-2 testing by quantitative real-time reverse-transcription PCR. Demographic, clinical, and epidemiologic characteristics of PUI were reported by public health and healthcare professionals during consultation with on-call CDC clinicians and subsequent submission of a CDC PUI Report Form. Characteristics of laboratory-negative and laboratory-positive persons were summarized as proportions for the period of January 17-February 29, and characteristics of all PUI were compared before and after February 12 using prevalence ratios. RESULTS: A total of 36 PUI tested positive for SARS-CoV-2 and were classified as confirmed cases. Confirmed cases and PUI testing negative for SARS-CoV-2 had similar demographic, clinical, and epidemiologic characteristics. Consistent with changes in PUI evaluation criteria, 88% (13/15) of confirmed cases detected before February 12, 2020, reported travel from China. After February 12, 57% (12/21) of confirmed cases reported no known travel- or contact-related exposures. CONCLUSIONS: These findings can inform preparedness for future pandemics, including capacity for rapid expansion of novel diagnostic tests to accommodate broad surveillance strategies to assess community transmission, including potential contributions from asymptomatic and presymptomatic infections.

Factors Associated with HIV Antiretroviral Therapy among Men Who Have Sex with Men in 20 US Cities, 2014.

Reducing HIV among men who have sex with men (MSM) is a national goal, and early diagnosis, timely linkage to HIV medical care, and ongoing care and treatment are critical for improving health outcomes for MSM with HIV and preventing transmission to others. We assessed demographic, social, and economic factors associated with HIV antiretroviral treatment among HIV-infected MSM. Data are from the National HIV Behavioral Surveillance (NHBS) collected in 2014 among MSM. We estimated prevalence ratios and 95% confidence intervals using average marginal predictions from logistic regression. Overall, 89% of HIV-positive MSM reported currently taking antiretroviral therapy (ART). After controlling for other variables, we found that higher perceived community stigma and not having health insurance were significant risk factors for not taking ART. We also found that high socioeconomic status (SES) was associated with taking ART. Race/ethnicity was not significantly associated with taking ART in either the unadjusted or adjusted analyses. Findings suggest that to increase ART use for MSM with HIV, we need to move beyond individual-level approaches and move towards the development, dissemination, and evaluation of structural and policy interventions that respond to these important social and economic factors.

HIV Testing, Linkage to HIV Medical Care, and Interviews for Partner Services Among Black Men Who Have Sex with Men - Non-Health Care Facilities, 20 Southern U.S. Jurisdictions, 2016.

Identifying HIV-infected persons who are unaware of their human immunodeficiency virus (HIV) infection status, linking them to care, and reducing health disparities are important national HIV prevention goals (1). Gay, bisexual, and other men who have sex with men (collectively referred to as MSM) accounted for 70% of HIV infection diagnoses in the United States in 2016, despite representing only 2% of the population (2,3). African American or black (black) MSM accounted for 38% of all new diagnoses of HIV infection among MSM (2). Nearly two thirds (63%) of all U.S. black MSM with diagnosed HIV infection reside in the southern United States (2), making targeted HIV prevention activities for black MSM in this region critical. Analysis of CDC-funded HIV testing data for black MSM submitted by 20 health departments in the southern United States in 2016 revealed that although black MSM received 6% of the HIV tests provided, they accounted for 36% of the new diagnoses in non-health care facilities. Among those who received new diagnoses, 67% were linked to HIV medical care within 90 days of diagnosis, which is below the 2020 national goal of linking at least 85% of persons with newly diagnosed HIV infection to care within 30 days (1). Black MSM in the southern United States are the group most affected by HIV, but only a small percentage of CDC tests in the southern United States are provided to this group. Increasing awareness of HIV status through HIV testing, especially among black MSM in the southern United States, is essential for reducing the risk for transmission and addressing disparities. HIV testing programs in the southern United States can reach more black MSM by conducting targeted risk-based testing in non-health care settings and by routine screening in agencies that also provide health care services to black MSM.

HIV Testing, Linkage to HIV Medical Care, and Interviews for Partner Services Among Women - 61 Health Department Jurisdictions, United States, Puerto Rico, and the U.S. Virgin Islands, 2015.

Diagnoses of human immunodeficiency virus (HIV) infection among women declined 17% during 2011-2015, and a total of 7,498 women received a diagnosis of HIV infection in 2015 (1). Although black or African American (black) women accounted for only 12% of the U.S. female population, 60% of women with newly diagnosed HIV infection were black (1,2). By the end of 2014, an estimated 255,900 women were living with HIV infection (3), including approximately 12% who did not know they were infected; in addition, approximately 45% of women who had received a diagnosis had not achieved viral suppression (3). HIV testing is an important public health strategy for identifying women with HIV infection and linking them to HIV medical care. Analysis of CDC-funded program data submitted by 61 health departments in 2015 indicated that among 4,749 women tested who received a diagnosis of HIV infection, 2,951 (62%) had received a diagnosis in the past (previous diagnosis), and 1,798 (38%) were receiving a diagnosis for the first time (new diagnosis). Of those who had received a previous diagnosis, 87% were not in HIV medical care at the time of the current test. Testing and identifying women who are living with HIV infection but who are not in care (regardless of when they received their first diagnosis) and rapidly linking them to care so they can receive antiretroviral therapy and become virally suppressed are essential for reducing HIV infection among all women.

HIV Transmission Dynamics Among Foreign-Born Persons in the United States.

BACKGROUND: In the United States (US), foreign-born persons are disproportionately affected by HIV and differ epidemiologically from US-born persons with diagnosed HIV infection. Understanding HIV transmission dynamics among foreign-born persons is important to guide HIV prevention efforts for these populations. We conducted molecular transmission network analysis to describe HIV transmission dynamics among foreign-born persons with diagnosed HIV. METHODS: Using HIV-1 polymerase nucleotide sequences reported to the US National HIV Surveillance System for persons with diagnosed HIV infection during 2001-2013, we constructed a genetic distance-based transmission network using HIV-TRACE and examined the birth region of potential transmission partners in this network. RESULTS: Of 77,686 people, 12,064 (16%) were foreign born. Overall, 28% of foreign-born persons linked to at least one other person in the transmission network. Of potential transmission partners, 62% were born in the United States, 31% were born in the same region as the foreign-born person, and 7% were born in another region of the world. Most transmission partners of male foreign-born persons (63%) were born in the United States, whereas most transmission partners of female foreign-borns (57%) were born in their same world region. DISCUSSION: These finding suggests that a majority of HIV infections among foreign-born persons in our network occurred after immigrating to the United States. Efforts to prevent HIV infection among foreign-born persons in the United States should include information of the transmission networks in which these individuals acquire or transmit HIV to develop more targeted HIV prevention interventions.

HIV testing in nonhealthcare facilities among adolescent MSM.

OBJECTIVES: To describe the extent to which Centers for Disease Control and Prevention (CDC)-funded HIV testing in nonhealthcare facilities reaches adolescent MSM, identifies new HIV infections, and links those newly diagnosed to medical care. METHODS/DESIGN: We describe HIV testing, newly diagnosed positivity, and linkage to medical care for adolescent MSM who received a CDC-funded HIV test in a nonhealthcare facility in 2015. We assess outcomes by race/ethnicity, HIV-related risk behaviors, and US geographical region. RESULTS: Of the 703 890 CDC-funded HIV testing events conducted in nonhealthcare facilities in 2015, 6848 (0.9%) were provided to adolescent MSM aged 13-19 years. Among those tested, 1.8% were newly diagnosed with HIV, compared with 0.7% among total tests provided in nonhealthcare facilities regardless of age and sex. The odds of testing positive among black adolescent MSM were nearly four times that of white adolescent MSM in multivariable analysis (odds ratio = 3.97, P < 0.001). Among adolescent MSM newly diagnosed with HIV, 67% were linked to HIV medical care. Linkage was lower among black (59%) and Hispanic/Latino adolescent MSM (71%) compared with white adolescent MSM (88%). CONCLUSION: CDC-funded nonhealthcare facilities can reach and provide HIV tests to adolescent MSM and identify new HIV infections; however, given the low rate of HIV testing overall and high engagement in HIV-related risk behaviors, there are opportunities to increase access to HIV testing and linkage to care for HIV-positive adolescent MSM. Efforts are needed to identify and address the barriers that prevent black and Hispanic/Latino adolescent MSM from being linked to HIV medical care in a timely manner.

The influence of urea and nitrate nutrients on the bioavailability and toxicity of nickel to Prorocentrum donghaiense (Dinophyta) and Skeletonema costatum (Bacillariophyta).

Nitrogen nutrients and nickel(Ni) are ubiquitous in aquatic environments, and they are important for primary production of ocean ecosystem. This study examined the interaction of nitrogen nutrients (specifically urea and nitrate) and Ni on chlorophyll (Chl a) concentration and photosynthesis parameters values of Prorocentrum donghaiense and Skeletonema costatum. The data presented here indicate that low concentration of Ni for P. donghaiense and S. costatum can enhance both Chl a concentration and photosynthesis parameters values when grown in urea containing environment. Despite this increase there was also an observed depression in both species tested when incubated in high concentration of Ni for P. donghaiense and S. costatum regardless of incubating in urea or nitrate. Additionally, EC50 values of Chl a and Fv/Fm for Ni at different time intervals were calculated in this study. These observations indicated that the Ni tolerance was higher in P. donghaiense as compared to S. costatum. The Ni tolerance of P. donghaiense incubated in urea was higher than that incubating in nitrate. The same phenomenon was not observed in S. costatum, which indicated that the influence of urea was dependent on the species investigated. Thus, urea input could impact Ni bioavailability and toxicity, and then affect the biodynamics thereafter.

A role for activated Cdc42 in glioblastoma multiforme invasion.

Cdc42 is a Rho-GTPase which plays a major role in regulating cell polarity and migration by specifying the localization of filopodia. However, the role of Cdc42 in GBM invasion has not been thoroughly investigated. We generated stable doxycycline-inducible clones expressing wild type (WT)-, constitutively active (CA)-, and dominant negative (DN)-Cdc42 in three different human glioma cell lines. Expression of CA-Cdc42 significantly increased the migration and invasive properties of malignant glioma cells compared to WT and DN-Cdc42 cell clones, and this was accompanied by a greater number of filopodia and focal adhesion structures which co-localize with phosphorylated focal adhesion kinase (FAK). By mass spectrometry and immunoprecipitation studies, we demonstrated that activated Cdc42 binds to IQGAP1. When implanted orthotopically in mice, the CA-Cdc42 expressing glioma cells exhibited enhanced local migration and invasion, and led to larger tumors, which significantly reduced survival. Using the Cancer Genome Atlas dataset, we determined that high Cdc42 expression is associated with poorer progression free survival, and that Cdc42 expression is highest in the proneural and neural subgroups of GBM. In summary, our studies demonstrate that activated Cdc42 is a critical determinant of the migratory and invasive phenotype of malignant gliomas, and that its effect may be mediated, at least in part, through its interaction with IQGAP1 and phosphorylated FAK.

Withania somnifera root extract inhibits mammary cancer metastasis and epithelial to mesenchymal transition.

Though clinicians can predict which patients are at risk for developing metastases, traditional therapies often prove ineffective and metastatic disease is the primary cause of cancer patient death; therefore, there is a need to develop anti-metastatic therapies that can be administered over long durations to specifically inhibit the motility of cancer cells. Withaniasomnifera root extracts (WRE) have anti-proliferative activity and the active component, Withaferin A, inhibits the pro-metastatic protein, vimentin. Vimentin is an intermediate filament protein and is part of the epithelial to mesenchymal transition (EMT) program to promote metastasis. Here, we determined whether WRE standardized to Withaferin A (sWRE) possesses anti-metastatic activity and whether it inhibits cancer motility via inhibition of vimentin and the EMT program. Several formulations of sWRE were created to enrich for Withaferin A and a stock solution of sWRE in EtOH could recover over 90% of the Withaferin A found in the original extract powder. This sWRE formulation inhibited breast cancer cell motility and invasion at concentrations less than 1µM while having negligible cytotoxicity at this dose. sWRE treatment disrupted vimentin morphology in cell lines, confirming its vimentin inhibitory activity. To determine if sWRE inhibited EMT, TGF-ß was used to induce EMT in MCF10A human mammary epithelial cells. In this case, sWRE prevented EMT induction and inhibited 3-D spheroid invasion. These studies were taken into a human xenograft and mouse mammary carcinoma model. In both models, sWRE and Withaferin A showed dose-dependent inhibition of tumor growth and metastatic lung nodule formation with minimal systemic toxicity. Taken together, these data support the hypothesis that low concentrations of sWRE inhibit cancer metastasis potentially through EMT inhibition. Moreover, these doses of sWRE have nearly no toxicity in normal mouse organs, suggesting the potential for clinical use of orally administered WRE capsules.

In vivo analysis of human nucleoporin repeat domain interactions.

The nuclear pore complex (NPC), assembled from ∼30 proteins termed nucleoporins (Nups), mediates selective nucleocytoplasmic trafficking. A subset of nucleoporins bear a domain with multiple phenylalanine-glycine (FG) motifs. As binding sites for transport receptors, FG Nups are critical in translocation through the NPC. Certain FG Nups are believed to associate via low-affinity, cohesive interactions to form the permeability barrier of the pore, although the form and composition of this functional barrier are debated. We used green fluorescent protein-Nup98/HoxA9 constructs with various numbers of repeats and also substituted FG domains from other nucleoporins for the Nup98 domain to directly compare cohesive interactions in live cells by fluorescence recovery after photobleaching (FRAP). We find that cohesion is a function of both number and type of FG repeats. Glycine-leucine-FG (GLFG) repeat domains are the most cohesive. FG domains from several human nucleoporins showed no interactions in this assay; however, Nup214, with numerous VFG motifs, displayed measurable cohesion by FRAP. The cohesive nature of a human nucleoporin did not necessarily correlate with that of its yeast orthologue. The Nup98 GLFG domain also functions in pore targeting through binding to Nup93, positioning the GLFG domain in the center of the NPC and supporting a role for this nucleoporin in the permeability barrier.

Nup98-homeodomain fusions interact with endogenous Nup98 during interphase and localize to kinetochores and chromosome arms during mitosis.

Chromosomal translocations involving the Nup98 gene are implicated in leukemias, especially acute myelogenous leukemia. These translocations generate chimeric fusion proteins, all of which have in common the N-terminal half of Nup98, which contains the nucleoporin FG/GLFG repeat motifs. The homeodomain group of Nup98 fusion proteins retain the C-terminus of a homeodomain transcription factor, including the homeobox responsible for DNA binding. Current models for Nup98 leukemogenesis invoke aberrant transcription resulting from recruitment of coregulators by the Nup98 repeat domain. Here we have investigated the behavior of Nup98-homeodomain fusion proteins throughout the cell cycle. At all stages, the fusion proteins exhibit a novel localization distinct from the component proteins or fragments. During interphase, there are dynamic interactions between the Nup98 fusions and endogenous Nup98 that lead to mislocalization of the intranuclear fraction of Nup98, but do not alter the level of Nup98 at the nuclear pore complex. During mitosis, no interaction between the fusion proteins and endogenous Nup98 is observed. However, the fusions are entirely concentrated at kinetochores and on chromosome arms, sites where the APC/C, a target of Nup98 regulation, is also found. Our observations suggest new possibilities for misregulation by which Nup98 translocations may contribute to cellular transformation and leukemogenesis.

Nuclear pore proteins and cancer.

Nucleocytoplasmic trafficking of macromolecules, a highly specific and tightly regulated process, occurs exclusively through the nuclear pore complex. This immense structure is assembled from approximately 30 proteins, termed nucleoporins. Here we discuss the four nucleoporins that have been linked to cancers, either through elevated expression in tumors (Nup88) or through involvement in chromosomal translocations that encode chimeric fusion proteins (Tpr, Nup98, Nup214). In each case we consider the normal function of the nucleoporin and its translocation partners, as well as what is known about their mechanistic contributions to carcinogenesis, particularly in leukemias. Studies of nucleoporin-linked cancers have revealed novel mechanisms of oncogenesis and in the future, should continue to expand our understanding of cancer biology.

Nup98 localizes to both nuclear and cytoplasmic sides of the nuclear pore and binds to two distinct nucleoporin subcomplexes.

The vertebrate nuclear pore is an enormous structure that spans the double membrane of the nuclear envelope. In yeast, most nucleoporins are found symmetrically on both the nuclear and cytoplasmic sides of the structure. However, in vertebrates most nucleoporins have been localized exclusively to one side of the nuclear pore. Herein, we show, by immunofluorescence and immunoelectron microscopy, that Nup98 is found on both sides of the pore complex. Additionally, we find that the pore-targeting domain of Nup98 interacts directly with the cytoplasmic nucleoporin Nup88, a component of the Nup214, Nup88, Nup62 subcomplex. Nup98 was previously described to interact with the nuclear-oriented Nup160, 133, 107, 96 complex through direct binding to Nup96. Interestingly, the same site within Nup98 is involved in binding to both Nup88 and Nup96. Autoproteolytic cleavage of the Nup98 C terminus is required for both of these binding interactions. When cleavage is blocked by a point mutation, a minimal eight amino acids downstream of the cleavage site is sufficient to prevent most binding to either Nup96 or Nup88. Thus, Nup98 interacts with both faces of the nuclear pore, a localization in keeping with its previously described nucleocytoplasmic shuttling activity.

The three-dimensional structure of the autoproteolytic, nuclear pore-targeting domain of the human nucleoporin Nup98.

Nup98 is a component of the nuclear pore that plays its primary role in the export of RNAs. Nup98 is expressed in two forms, derived from alternate mRNA splicing. Both forms are processed into two peptides through autoproteolysis mediated by the C-terminal domain of hNup98. The three-dimensional structure of the C-terminal domain reveals a novel protein fold, and thus a new class of autocatalytic proteases. The structure further reveals that the suggested nucleoporin RNA binding motif is unlikely to bind to RNA. The C terminus also contains sequences that target hNup98 to the nuclear pore complex. Noncovalent interactions between the C-terminal domain and the cleaved peptide tail are visible and suggest a model for cleavage-dependent targeting of hNup98 to the nuclear pore.

Interaction of p58(PITSLRE), a G2/M-specific protein kinase, with cyclin D3.

The p58(PITSLRE) is a p34(cdc2)-related protein kinase that plays an important role in normal cell cycle progression. Elevated expression of p58(PITSLRE) in eukaryotic cells prevents them from undergoing normal cytokinesis and appears to delay them in late telophase. To investigate the molecular mechanism of p58(PITSLRE) action, we used the yeast two-hybrid system, screened a human fetal liver cDNA library, and identified cyclin D3 as an interacting partner of p58(PITSLRE). In vitro binding assay, in vivo coimmunoprecipitation, and immunofluorescence cell staining further confirmed the association of p58(PITSLRE) with cyclin D3. This binding was observed only in the G(2)/M phase but not in the G(1)/S phase of the cell cycle; meanwhile, no interaction between p110(PITSLRE) and cyclin D3 was observed in all the cell cycle. The overexpression of cyclin D3 in 7721 cells leads to an exclusively accumulation of p58(PITSLRE) in the nuclear region, affecting its cellular distribution. Histone H1 kinase activity of p58(PITSLRE) was greatly enhanced upon interaction with cyclin D3. Furthermore, kinase activity of p58(PITSLRE) was found to increase greatly in the presence of cyclin D3 using a specific substrate, beta-1,4-galactosyltransferase 1. These data provide a new clue to our understanding of the cellular function of p58(PITSLRE) and cyclin D3.