Nasopharyngeal carcinoma is highly prevalent in Southern China and Southeast Asia. To unveil the molecular basis of this endemic disease, high-resolution comparative genomic hybridization arrays were used for systematic investigation of genomic abnormalities in 26 nasopharyngeal carcinoma samples. A comprehensive picture of genetic lesions associated with tumorigenesis of nasopharyngeal carcinoma was generated. Consistent chromosomal gains were frequently found on 1q, 3q, 8q, 11q, 12p, and 12q. High incidences of nonrandom losses were identified on chromosomes 3p, 9p, 11q, 14q, and 16q. In addition to previously characterized regions, we have identified several novel minimal regions of gains, including 3q27.3-28, 8q21-24, 11q13.1-13.3, and 12q13, which may harbor candidate nasopharyngeal carcinomaassociated oncogenes. In this study, gain of 11q13.1-13.3 was the most frequently detected chromosomal aberration and a 5.3-Mb amplicon was delineated at this region. Within this 11q13 amplicon, concordant amplification and overexpression of cyclin D1 (CCND1) oncogene was found in nasopharyngeal carcinoma cell lines, xenografts, and primary tumors. Knockdown of cyclin D1 by small interfering RNA in nasopharyngeal carcinoma cell lines led to significant decrease of cell proliferation. The findings suggest that cyclin D1 is a target oncogene at 11q13 in nasopharyngeal carcinoma and its activation plays a significant role in nasopharyngeal carcinoma tumorigenesis. (Cancer Res 2005; 65(18): 8125-33)

The “other-race” effect describes the phenomenon in which faces are difficult to distinguish from one another if they belong to an ethnic or racial group to which the observer has had little exposure. Adult observers typically display multiple forms of recognition error for other-race faces, and infants exhibit behavioral evidence of a developing other-race effect at about 9 months of age. The neural correlates of the adult other-race effect have been identified using ERPs and fMRI, but the effects of racial category on infants’ neural response to face stimuli have to date not been described. We examine two distinct components of the infant ERP response to human faces and demonstrate through the use of computer-generated “hybrid” faces that the observed other-race effect is not the result of low-level sensitivity to 3D shape and color differences between the stimuli. Rather, differential processing depends critically on the joint encoding of race-specific features.

The human papillomavirus (HPV) E7 oncoprotein exists as a dimer and acts by binding to many cellular factors, preventing or retargeting their function and thereby making the infected cell conducive for viral replication. Dimerization of E7 is attributed primarily to the C-terminal domain, referred to as conserved region 3 (CR3). CR3 is highly structured and is necessary for E7's transformation ability. It is also required for binding of numerous E7 cellular targets. To systematically analyze the molecular mechanisms by which HPV16 E7 CR3 contributes to carcinogenesis, we created a comprehensive panel of mutations in residues predicted to be exposed on the surface of CR3. We analyzed our novel collection of mutants, as well as mutants targeting predicted hydrophobic core residues of the dimer, for the ability to dimerize. The same set of mutants was also assessed functionally for transformation capability in a baby rat kidney cell assay in conjugation with activated ras. We show that some mutants of HPV16 E7 CR3 failed to dimerize yet were still able to transform baby rat kidney cells. Our results identify several novel E7 mutants that abrogate transformation and also indicate that E7 does not need to exist as a stable dimer in order to transform cells.More than 100 human papillomavirus (HPV) types have been described, and more are presumed to exist (16). HPVs induce papillomas in the cutaneous and mucosal epithelia, where specific HPV types often preferentially infect distinct anatomical sites. HPVs associated with lesions that can progress to carcinogenesis are classified as "high-risk" types, the most common of which is HPV16. In contrast, HPVs associated with benign warts that regress with time are termed "lowrisk" viruses (50). Persistent infection by high-risk HPVs is associated with 99.7% of all human cervical cancer cases (15), other genitourinary cancers, and an increasingly growing number of oral cancers (21).The viral E6 and E7 oncoproteins are consistently expressed in HPV-induced cancers and are necessary to maintain malignant cell growth (3,6,29,42,43). Repression of their transcription by reexpression of the viral E2 protein induces rapid growth arrest and senescence of cervical cancer cells (22,23). The HPV E7 oncoprotein binds the product of the retinoblastoma susceptibility locus (pRb) and the related family members p107 and p130 (17). These proteins function as tumor suppressors, maintaining control of the G 1 /S checkpoint of the cell cycle by binding to the E2F family of transcription factors and by recruiting transcriptional repressor complexes to the E2F-responsive genes (10, 36). Besides pRb, the E7 oncoproteins from high-risk HPV types abrogate the inhibitory activities of the cyclin-dependent kinase inhibitors p21 and p27 by directly binding these factors (19,48). E7 interacts with the pCAF acetyltransferase, the Mi2␤ subunit of the NuRD histone deacetylase complex, the S4 component of the 26S proteasome, the HIF-1␣ and E2F6 transcription factors, and many other important cellular protei...

The human papillomavirus (HPV) E7 oncoprotein binds cellular factors, preventing or retargeting their function and thereby making the infected cell conducive for viral replication. A key target of E7 is the product of the retinoblastoma susceptibility locus (pRb). This interaction results in the release of E2F transcription factors and drives the host cell into the S phase of the cell cycle. E7 binds pRb via a high-affinity binding site in conserved region 2 (CR2) and also targets a portion of cellular pRb for degradation via the proteasome. Evidence suggests that a secondary binding site exists in CR3, and that this interaction influences pRb deregulation. Additionally, evidence suggests that CR3 also participates in the degradation of pRb. We have systematically analyzed the molecular mechanisms by which CR3 contributes to deregulation of the pRb pathway by utilizing a comprehensive series of mutations in residues predicted to be exposed on the surface of HPV16 E7 CR3. Despite differences in the ability to interact with cullin 2, all CR3 mutants degrade pRb comparably to wild-type E7. We identified two specific patches of residues on the surface of CR3 that contribute to pRb binding independently of the high-affinity CR2 binding site. Mutants within CR3 that affect pRb binding are less effective than the wild-type E7 in overcoming pRb-induced cell cycle arrest. This demonstrates that the interaction between HPV16 E7 CR3 and pRb is functionally important for alteration of the cell cycle. Papillomaviruses are a group of DNA viruses that infect the skin and mucosal tissues of most vertebrates. More than 100 human papillomavirus (HPV) types have been identified, but far more are presumed to exist (21). A subset of HPVs is associated with lesions that frequently progress to cancer, and these HPVs are classified as high-risk types. Persistent infection by high-risk HPVs is related to 99.7% of all human cervical cancer cases (20), other genitourinary cancers, and a growing number of oral cancers (31). Although recently developed vaccines protect individuals from the two most frequently carcinogenic HPV types, HPV16 and HPV18, they offer limited protection against other cancercausing HPVs and provide no benefit to individuals with a preexisting history of infection (13,28,48). The development of other therapies to treat HPV-induced malignancy may be facilitated by a greater understanding of the mechanisms of virally mediated cellular transformation.The viral E6 and E7 oncoproteins are consistently expressed in HPV-induced cancers and are necessary to maintain malignant cell growth (2, 4, 37, 49, 51). Repression of their transcription by reexpression of the viral E2 regulatory protein induces rapid growth arrest and senescence of cervical cancer cells, suggesting that these cancer cells are addicted to E6 and E7 (33, 34). The HPV E7 protein is a multifunctional oncoprotein that interacts with a multitude of cellular factors (3,6,8,11,53). One of the main activities of E7 is to induce terminally differentiated cells to ...