Detection of human papillomavirus in the oral cavities of persons with Fanconi anemia.

OBJECTIVE: We conducted a cross-sectional study to describe the prevalence and correlates of type-specific human papillomavirus (HPV) DNA in the oral cavities of persons with Fanconi anemia. MATERIALS AND METHODS: Oral swabs were collected from 67 participants with Fanconi anemia and tested for 27 HPV genotypes using polymerase chain reaction-based methods. RESULTS: Participants were a mean of 18.6 (standard deviation, 10.0) years of age (range 4-47 years). The prevalence of oral HPV infection was 7.5%, and the prevalence of high-risk HPV infection was 6.0%. HPV type 16 was not detected in any samples. Prevalence was higher in adults than in children (13.3% vs 2.7% in those ≥18 vs <18 years of age). Among adults, prevalence was higher in males than in females (25.0% vs 9.1%, respectively). CONCLUSIONS: Prevalence of oral HPV infection in persons with Fanconi anemia was comparable to estimates from other studies in the general population. However, in contrast to previous studies, we did not identify HPV type 16 (the type found in most HPV-related head and neck cancers) in any participants.

Human leukocyte antigen class II alleles in Caucasian women with primary biliary cirrhosis.

In the current study, we investigated human leukocyte antigen (HLA) class II alleles in Caucasian women with primary biliary cirrhosis (PBC), a disease that preferentially affects women. Alleles of DRB1, DQA1, and DQB1 were determined by DNA-based HLA typing for women with PBC (n = 72) and healthy women (n = 381). All study subjects were Caucasian. HLA DRB1*08 was significantly increased in women with PBC compared to healthy women. The increase was primarily due to the DRB1*0801 allele, also the most common DRB1*08 allele among controls. DQB1*04 and DQA1*0401 were significantly increased. DRB1*1501, DQA1*0102, and DQB1*0602 were associated with decreased risk. Analyses conducted comparing parous women with PBC to parous healthy women (n = 68 and n = 282, respectively) yielded similar significant results. Although the DRB1*08-DQA1*0401-DQB1*04 haplotype was significantly associated with PBC, consistent with other studies, this haplotype nevertheless represented only 19% (14/72) of all PBC patients and can account for only a minority of the risk of PBC.

Regulation of telomerase by human papillomaviruses.

The E6 oncoprotein of human papillomaviruses (HPVs) induces telomerase activity in primary human epithelial cells. This activity is dependent on association of E6 with E6AP, a cellular ubiquitin ligase. E6 activates the transcription of hTERT, the catalytic subunit of telomerase. E boxes near the start of hTERT transcription are required for E6; however, acetylated histones are only present in the E6 cells. We identified two isoforms of NFX1, a new binding partner of E6/E6AP. The NFX1- 91 isoform binds to an X-box motif located adjacent to the proximal E box, binds Sin3A and HDACs, repressing hTERT transcription. It preferentially binds E6/E6AP and is targeted for ubiquitin-mediated degradation. The NFX1-123 isoform has the opposite activity, increasing hTERT transcription or translation. This is the first example of viral oncoproteins disrupting regulation of telomerase, a critical event in tumorigenesis.

HLA allelic variants encoding DR11 in diffuse and limited systemic sclerosis in Caucasian women.

OBJECTIVE: We investigated HLA class II alleles in women with systemic sclerosis (SSc), a rare disease that preferentially affects women. METHODS: Specific alleles of DRB1, DQA1 and DQB1 were determined by DNA-based HLA typing for women with SSc (n = 102) and healthy women (n = 533). All study subjects were Caucasian. DRB1, DQA1 and DQB1 allele frequencies of women with SSc were compared with those of healthy women. RESULTS: Among women with SSc, 29.4% (30/102) and among healthy women 10.7% (57/533) had DRB1*11. Allele frequencies were compared for women with SSc and healthy women (each woman has two alleles). The allele frequency of DRB1*11 was 15.7% (32/204 alleles) in SSc women and 5.8% (62/1066 alleles) in healthy women (P = 0.000002). The increase of DRB1*11 was found both in diffuse (P = 0.0001) and limited SSc (P = 0.002) (allele frequencies 15.0 and 17.2%, respectively). Among women with diffuse SSc, there was a disproportionate increase of the DRB1*1104 allele (P = 0.0004) with no increase of DRB1*1101 (P = 1.00). In contrast, in limited SSc the strongest association was with DRB1*1101 (P = 0.008), with a less significant increase of DRB1*1104 (P = 0.04). CONCLUSIONS: An increase of DRB1*11 in SSc is consistent with other reports. Although present in both diffuse and limited SSc disease subsets, the increase was predominantly due to over-representation of DRB1*1104 in women with diffuse SSc. Women with limited SSc had a preponderance of DRB1*1101, the most common allele in healthy women. DRB1*1104 and DRB1*1101 differ by a single amino acid at position 86, where the former has valine and the latter glycine.

Serologic evidence of herpes simplex virus 1 infection and oropharyngeal cancer risk.

In vitro and animal models suggest that the herpes simplex virus 1 (HSV1) may contribute to the development of oropharyngeal squamous cell carcinoma (OSCC). To determine whether the risk of OSCC is related to infection with HSV1 in humans, we recruited 260 patients from 18 to 65 years old who were newly diagnosed with OSCC between 1990-1995 while residing in three western Washington State counties. For comparison, we recruited at random 445 controls frequency matched to cases on age and sex. Participants completed in-person interviews and provided serum samples that were tested for antibody response to HSV1. After adjusting for sex, cigarette smoking, alcohol consumption, age, and income, HSV1 antibody positivity was associated with a slightly increased risk of OSCC [adjusted odds ratio (OR), 1.3; 95% confidence interval (CI), 0.9-2.0]. The adjusted association between HSV1 antibody positivity and OSCC risk among those who were current cigarette smokers (OR, 4.2; CI, 2.4-7.1) was stronger than would be predicted based on the additive combination of smoking alone (OR, 2.3; CI, 1.2-4.2) and HSV1 seropositivity alone (OR, 1.0; CI, 0.6-1.7). There was suggestive evidence that the association between HSV1 infection and OSCC was similarly modified by evidence of HPV infection but no evidence of effect modification with alcohol consumption. This population-based study suggests that HSV1 may enhance the development of OSCC in individuals who are already at increased risk of the disease because of cigarette smoking or HPV infection.

Destabilization of the retinoblastoma tumor suppressor by human papillomavirus type 16 E7 is not sufficient to overcome cell cycle arrest in human keratinocytes.

The E7 oncoprotein of human papillomavirus type 16 promotes cell proliferation in the presence of antiproliferative signals. Mutagenesis of E7 has revealed that this activity requires three regions, conserved regions 1 and 2 and a C-terminal zinc finger. Binding to the retinoblastoma tumor repressor (Rb) through an LxCxE motif in conserved region 2 is necessary, but not sufficient, for E7 to induce proliferation. We tested the hypothesis that binding to Rb is not sufficient because conserved region 1 and/or the C terminus are required for E7 to functionally inactivate Rb and thus induce proliferation. One mechanism proposed for how E7 inactivates Rb is by blocking Rb-E2F binding. Either conserved region 1 or the C terminus was necessary, in combination with the LxCxE motif, for E7 to block Rb-E2F binding in vitro. While all full-length E7 proteins with mutations outside of the LxCxE motif inhibited Rb-E2F binding, some failed to abrogate cell cycle arrest, demonstrating that blocking Rb-E2F binding is not sufficient for abrogating antiproliferative signals. Another mechanism proposed for how E7 inactivates Rb is by promoting the destabilization of Rb protein. Mutations in conserved region 1 or the LxCxE motif prevented E7 from reducing the half-life of Rb. Though no specific C-terminal residues of E7 were essential for destabilizing Rb, a novel class of mutations that uncouple the destabilization of Rb from the deregulation of keratinocyte proliferation was discovered. Destabilization of Rb correlated with the abrogation of Rb-induced quiescence but was not sufficient for overriding DNA damage-induced cell cycle arrest or for increasing keratinocyte life span. Finally, the same regions of E7 required for destabilizing Rb were required for reducing p107 and p130 levels. Together, these results suggest that inactivation of all three Rb family members is not sufficient to deregulate keratinocyte cell cycle control.

E box-dependent activation of telomerase by human papillomavirus type 16 E6 does not require induction of c-myc.

Human papillomavirus type 16 (HPV-16) E6 activates telomerase specifically in epithelial cells. The oncogene c-myc has also been shown to activate telomerase in several cell types. Here we show that while both HPV-16 E6 and c-myc require intact E boxes to transactivate the hTERT promoter, E6 does not induce hTERT transcription simply by inducing expression of c-myc. Moreover, hTERT transactivation by HPV-16 E6 correlates with its ability to bind the cellular E6-associated protein (E6AP), suggesting that E6 and E6AP may target a regulator of hTERT expression.

Human papillomavirus and prognosis of invasive cervical cancer: a population-based study.

PURPOSE: To determine the association between human papillomavirus (HPV) type and prognosis of patients with invasive cervical carcinoma. PATIENTS AND METHODS: Patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IB to IV cervical cancer between 1986 and 1997 while residents of three Washington State counties were included (n = 399). HPV typing was performed on paraffin-embedded tumor tissue using polymerase chain reaction methods. Patients were observed for a median of 50.8 months. Total mortality (TM) and cervical cancer-specific mortality (CCSM) were determined. Hazards ratios (HR) adjusted for age, stage, and histologic type were estimated using multivariable models. RESULTS: Eighty-six patients had HPV 18-related tumors and 210 patients had HPV 16-related tumors. Cumulative TM among patients with HPV 18-related tumors and among patients with HPV 16-related tumors were 33.7% and 27.6%, respectively; cumulative CCSM in these two groups were 26.7% and 18.1%, respectively. Compared with patients with HPV 16-related cancers, patients with HPV 18-related cancers were at increased risk for TM (HR(TM), 2.2; 95% confidence interval [CI], 1.3 to 3.6) and CCSM (HR(CCSM), 2.5; 95% CI, 1.4 to 4.4). The HPV18 associations were strongest for patients with FIGO stage IB or IIA disease (HR(TM), 3.1; 95% CI, 2.3 to 4.2; and HR(CCSM), 5.8; 95% CI, 3.9 to 8.7), whereas no associations were observed among patients with FIGO stage IIB to IV disease. Virtually identical associations were found in the subset of patients with squamous cell carcinoma (n = 219). CONCLUSION: HPV 18-related cervical carcinomas, particularly those diagnosed at an early stage, are associated with a poor prognosis. Elucidating the mechanism or mechanisms underlying this association could lead to new treatment approaches for patients with invasive cervical carcinoma.

Human papillomavirus and long-term oral contraceptive use increase the risk of adenocarcinoma in situ of the cervix.

We examined United States Surveillance, Epidemiology, and End Results incidence data and conducted a population-based case-control study to examine the role of human papillomavirus (HPV) and oral contraceptive (OC) use in the etiology of adenocarcinoma in situ of the cervix (ACIS). One hundred and fifty women diagnosed with ACIS and 651 randomly selected control women completed in-person interviews. The presence of HPV DNA in archival ACIS specimens was determined by E6 and L1 consensus PCR. Serum samples from case and control subjects were collected at interview, and antibodies to HPV-16 L1 and HPV-18 L1 were detected by virus-like particle capture assays. The overall prevalence of HPV DNA was 86.6%, with 39.0% positive for HPV-16 DNA, 52.4% positive for HPV-18 DNA, and 13.4% positive for more than one HPV type. The age-adjusted relative risk of ACIS associated with HPV-18 seropositivity was 3.3 (95% confidence interval 2.2-4.9). No increased risk was associated with antibodies to HPV-16 L1. Among women born after 1945, the relative risk increased with duration of OC use, with the highest risk for 12 or more years of use (odds ratio, 5.5; 95% confidence interval, 2.1-14.6) relative to nonusers. The detection of HPV DNA in 86.6% of ACIS and the strong association of ACIS with HPV-18 L1 seropositivity underscore the importance of HPV, particularly HPV-18, in the etiology of ACIS. In addition, long-term OC use may contribute to the pathogenesis of these tumors in some women.

Human papillomavirus 16 and 18 L1 serology compared across anogenital cancer sites.

Human papillomavirus (HPV) DNA has been detected in the great majority of cancers of the uterine cervix and anus, whereas the association of HPV DNA with cancer at other anogenital sites has produced less consistent results. This study was designed to compare HPV exposure among anogenital cancer cases and matched controls. Cases (1782) of anogenital cancer diagnosed in the Seattle area from 1978 to 1998 were identified and interviewed. Their responses were compared with those of 2383 age- and sex-matched controls. Blood was drawn at interview from both cases and controls and tested for antibodies to HPV-16 and HPV-18. Tissue blocks were tested for HPV DNA for 649 cases. Serum antibodies to HPV-16 were associated with in situ and invasive cancer at all sites among men and women with the exception of in situ penile cancer. Anti-HPV-18 antibodies were associated with cancers at all sites among women. The increased risk of cancer associated with HPV-16 seropositivity ranged from odds ratio = 1.8 (95% confidence interval, 1.4-2.5) for adenocarcinoma of the cervix to odds ratio = 5.9 (95% confidence interval, 3.4-10.3) for anal cancer in men. Associations between seroprevalence and cancers were stronger when analyses were restricted to HPV-16- or HPV-18 DNA-positive cases. HPV DNA was detected in >80% of cancers from all sites tested. HPV-16 DNA was the type most frequently detected at all sites (range, 40.9-82.2%). HPV-18 DNA was detected in 44.7% of adenocarcinomas of the cervix but detected much less often (2.6-18.1%) at other sites. These findings support an important role for HPV infection in anogenital cancer at all sites. Differences in the proportion of seropositives among HPV-16 DNA-positive cases by site suggest either that the immune response varies by site or that cancer development may lead to changes in antibody responses in a site-specific fashion.

Comparison of human papillomavirus types 16, 18, and 6 capsid antibody responses following incident infection.

The relationship between human papillomavirus (HPV) DNA in the genital mucosa and serum IgG to HPV-16, -18, and -6 was studied in a cohort of 588 college women. Among women with incident HPV infections, 59.5%, 54.1%, and 68.8% seroconverted for HPV-16, -18, or -6, respectively, within 18 months of detecting the corresponding HPV DNA. Transient HPV DNA was associated with a failure to seroconvert following incident HPV infection; however, some women with persistent HPV DNA never seroconverted. Antibody responses to each type were heterogeneous, but several type-specific differences were found: seroconversion for HPV-16 occurred most frequently between 6 and 12 months of DNA detection, but seroconversion for HPV-6 coincided with DNA detection. Additionally, antibody responses to HPV-16 and -18 were significantly more likely to persist during follow-up than were antibodies to HPV-6.

Identification of CIP-1-associated regulator of cyclin B (CARB), a novel p21-binding protein acting in the G2 phase of the cell cycle.

The cyclin-dependent kinase inhibitor p21(cip1) regulates cell cycle progression, DNA replication, and DNA repair by binding to specific cellular proteins through distinct amino- and carboxyl-terminal protein binding motifs. We have identified a novel human gene, CARB (CIP-1-associated regulator of cyclin B), whose product interacts with the p21 carboxyl terminus. Immunocytochemical analysis demonstrates that the CARB protein is perinuclear and predominantly associated with the centrosome and mitotic spindle poles. In addition, CARB is also able to associate with cyclin B1, a key regulator of mitosis. However, cyclin B1-CARB complex formation occurs preferentially in the absence of p21. Unexpectedly, overexpression of CARB is associated with a growth-inhibitory and ultimately lethal phenotype in p21(-/-) cells but not in p21(+/+) cells. These data identify a novel mechanism that may underlie the effects of p21 in the G(2)/M phases of the cell cycle.

Detection of cervical antibodies to human papillomavirus type 16 (HPV-16) capsid antigens in relation to detection of HPV-16 DNA and cervical lesions.

A more sensitive luminescence immunoassay (LIA) for human papillomavirus type 16 (HPV-16) was developed and used to measure HPV-16 antibodies in cervical samples from 292 college-aged women who were examined at 4-month intervals. Of the 609 collected samples, IgG, IgA, and secretory piece-associated antibodies to HPV-16 were detected in 12%, 6%, and 8%, respectively, of samples tested. Cervical IgG antibodies were most strongly associated with HPV-16 DNA detected within the previous 12 months (odds ratio, 3.3; 95% confidence interval, 1.4-7.8). Secretory IgA (cervical IgA- and secretory piece-positive) was most strongly associated with detection of a squamous intraepithelial lesions 4-8 months earlier (odds ratio, 6.4; 95% confidence interval, 1.9-21.8). As with serum HPV-16 antibodies, there appears to be a several-month delay between cervical HPV infection and detection of cervical antibodies.

The p53 Arg72Pro polymorphism, human papillomavirus, and invasive squamous cell cervical cancer.

A. Storey et al. [Nature (Lond.), 393: 229-234, 1998)] reported a 7-fold increased risk of cervical cancer associated with having an Arg/Arg polymorphism at codon 72 of p53 compared with the Pro/Arg heterozygotes (odds ratio, 7.4; 95% confidence interval, 2.1-29.4). Complementary in vitro studies suggested that the HPV E6 oncoprotein more readily targets the arginine form, as opposed to the proline form, of p53 for degradation. We investigated the impact of this polymorphism in a population-based case-control study of invasive cervical cancer. Using a PCR assay to detect the p53 codon 72 polymorphism, we tested blood samples from 111 women with invasive squamous cell cancer of the cervix identified by a population-based registry and 164 random-digit telephone-dialed controls. The distribution of the genotype among control women was 38% heterozygous, 7% proline homozygous, and 55% arginine homozygous, and among the cases was 38%, 6%, and 56%, respectively. There was no increased risk of squamous cell invasive cervical cancer associated with homozygosity for the arginine allele (odds ratio, 1.0; 95% confidence interval, 0.6-1.7). Furthermore, there was no modification of this result by human papillomavirus (HPV) DNA status of the tumor, age, or smoking status. Among controls, there was no association between the polymorphism and HPV-16 L1 seropositivity. However, among case subjects, the codon 72 polymorphism may be related to HPV 16L1 seropositivity status.

The G(2) checkpoint is maintained by redundant pathways.

While p53 activity is critical for a DNA damage-induced G(1) checkpoint, its role in the G(2) checkpoint has not been compelling because cells lacking p53 retain the ability to arrest in G(2) following DNA damage. Comparison between normal human foreskin fibroblasts (HFFs) and HFFs in which p53 was eliminated by transduction with human papillomavirus type 16 E6 showed that treatment with adriamycin initiated arrest in G(2) with active cyclin B/CDC2 kinase, regardless of p53 status. Both E6-transduced HFFs and control (LXSN)-transduced cells maintained a prolonged arrest in G(2); however cells with functional p53 extinguished cyclin B-associated kinase activity. Down regulation was mediated by p53-dependent transcriptional repression of the CDC2 and cyclin B promoters. In contrast, cells lacking p53 showed a prolonged G(2) arrest despite high levels of cyclin B/CDC2 kinase activity, at least some of which translocated into the nucleus. Furthermore, the G(2) checkpoint became attenuated as p53-deficient cells aged in culture. Thus, at late passage, E6-transduced HFFs entered mitosis following DNA damage, whereas the age-matched parental HFFs sustained a G(2) arrest. These results indicate that normal cells have p53-independent pathways to maintain DNA damage-induced G(2) arrest, which may be augmented by p53-dependent functions, and that cells lacking p53 are at greater risk of losing the pathway that protects against aneuploidy.

Progressive region-specific de novo methylation of the p16 CpG island in primary human mammary epithelial cell strains during escape from M(0) growth arrest.

CpG island methylation plays an important role in normal cellular processes, such as genomic imprinting and X-chromosome inactivation, as well as in abnormal processes, such as neoplasia. However, the dynamics of de novo CpG island methylation, during which a CpG island is converted from an unmethylated, active state to a densely methylated, inactive state, are largely unknown. It is unclear whether the development of de novo CpG island methylation is a progressive process, in which a subset of CpG sites are initially methylated with a subsequent increase in methylation density, or a single event, in which the initial methylation event encompasses the entire CpG island. The tumor suppressor gene p16/CDKN2a/INK4a (p16) is inactivated by CpG island methylation during neoplastic progression in a variety of human cancers. We investigated the development of methylation in the p16 CpG island in primary human mammary epithelial cell strains during escape from mortality stage 0 (M(0)) growth arrest. The methylation status of 47 CpG sites in the p16 CpG island on individual DNA molecules was determined by sequencing PCR clones of bisulfite-treated genomic DNA. The p16 CpG island was initially methylated at a subset of sites in three discrete regions in association with p16 transcriptional repression and escape from M(0) growth arrest. With continued passage, methylation gradually increased in density and methylation expanded to sites in adjacent regions. Thus, de novo methylation in the p16 CpG island is a progressive process that is neither site specific nor completely random but instead is region specific. Our results suggest that early detection of methylation in the CpG island of the p16 gene will require methylation analysis of the three regions and that the identification of region-specific methylation patterns in other genes may be essential for an accurate assessment of methylation-mediated transcriptional silencing.

Genital human papillomavirus infection in women who have sex with women.

Genital infection with human papillomavirus (HPV), as determined by polymerase chain reaction detection of HPV DNA and prevalence of HPV-6 and -16 serum antibodies, was investigated in 149 women who were sexually active with women. By use of HPV L1 consensus primers and hybridization to types 6/11, 16, 18, 31/33/35/39, and 45 and a generic probe, HPV DNA was detected in 30% of subjects; of these, 20% had type 31/33/35/39, 18% had type 16, and 2% had type 6/11. Of 21 subjects reporting no prior sex with men, HPV DNA was detected in 19% and squamous intraepithelial lesions in 14%. By capture ELISA with HPV-6 and -16 L1 capsids, 47% of subjects were seropositive for HPV-16 and 62% for HPV-6. Current smoking was associated with detectable HPV DNA. Genital HPV infection and squamous intraepithelial lesions are common among women who are sexually active with women and occur among those who have not had sex with men.

Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells.

Normal human cells undergo a limited number of divisions in culture and enter a non-dividing state called replicative senescence. Senescence is accompanied by several changes, including an increase in inhibitors of cyclin-dependent kinases and telomere shortening. The mechanisms by which viral oncogenes reverse these processes are not fully understood, although a general requirement for oncoproteins such as human papillomavirus E6 and E7 has suggested that the p53 and Rb pathways are targeted. Expression of the catalytic component of telomerase, hTERT, alone significantly extends the lifespan of human fibroblasts. Here we show that telomerase activity is not sufficient for immortalization of human keratinocyte or mammary epithelial cells: we find that neither addition of hTERT nor induction of telomerase activity by E6, both of which are active in maintaining telomere length, results in immortalization. Inactivation of the Rb/p16 pathway by E7 or downregulation of p16 expression, in combination with telomerase activity, however, is able to immortalize epithelial cells efficiently. Elimination of p53 and of the DNA-damage-induced G1 checkpoint is not necessary for immortalization, neither is elimination of p19ARF.

Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection.

BACKGROUND: Experimental models and analyses of human tumors suggest that oncogenic, sexually transmittable human papillomaviruses (HPVs) are etiologic factors in the development of oral squamous cell carcinoma (SCC). We conducted a population-based, case-control study to determine whether the risk of this cancer is related to HPV infection and sexual history factors. METHODS: Case subjects (n = 284) were 18-65-year-old residents of three counties in western Washington State who were newly diagnosed with oral SCC from 1990 through 1995. Control subjects (n = 477) similar in age and sex were selected from the general population. Serum samples were tested for HPV type 16 capsid antibodies. Exfoliated oral tissue collected from case and control subjects and tumor tissue from case subjects were tested for HPV DNA. Odds ratios (ORs) were calculated after adjusting for age, sex, cigarette smoking, and alcohol consumption. RESULTS: Among males only, oral SCC risk increased with self-reported decreasing age at first intercourse, increasing number of sex partners, and a history of genital warts. Approximately 26% of the tumors in case subjects contained HPV DNA; 16.5% of the tumors contained HPV type 16 DNA. The prevalence of oncogenic HPV types in exfoliated oral tissue was similar in case and control subjects. The ORs for HPV type 16 capsid seropositivity were 2.3 (95% confidence interval [CI] = 1.6-3.3) for all oral SCCs and 6.8 (95% CI = 3.0-15.2) for oral SCCs containing HPV type 16 DNA. The joint association of cigarette smoking and HPV type 16 capsid seropositivity with oral SCC (OR = 8.5; 95% CI = 5.1-14.4) was stronger than predicted from the sum of individual associations with current smoking (OR = 3.2; 95% CI = 2.0-5.2) and seropositivity (OR = 1.7; 95% CI = 1.1-2.6). CONCLUSIONS: HPV type 16 infection may contribute to the development of a small proportion of oral SCCs in this population, most likely in combination with cigarette smoking.

Inhibiting CDK inhibitors: new lessons from DNA tumor viruses.

The ability of viral oncoproteins to inactivate the retinoblastoma and p53 tumor suppressors provides mechanisms for bypassing the normal inhibitory activities of cyclin-dependent-kinase inhibitors (CKIs). Recent studies point to novel mechanisms for inhibiting the activities of the CKIs p21CIP1 and p27KIP1 activity. Such mechanisms involve the binding of viral oncoproteins or other proteins to these CKIs and suggest a model in which the cell-cycle activities of p21CIP1 are coordinated through protein-protein interactions.