The causal role of human papillomavirus infections in cervical cancer has been documented beyond reasonable doubt. The association is present in virtually all cervical cancer cases worldwide. It is the right time for medical societies and public health regulators to consider this evidence and to define its preventive and clinical implications. A comprehensive review of key studies and results is presented.

https://jcp.bmj.com/content/jclinpath/55/4/244.full.pdf

The causal relation between human papillomavirus and cervical cancer

Matrix metalloproteinases are an important group of zinc enzymes responsible for degradation of the extracellular matrix components such as collagen and proteoglycans in normal embryogenesis and remodeling and in many disease processes such as arthritis, cancer, periodontitis, and osteoporosis. A matrixin family is defined, comprising at least seven members that range in size from Mr 28,000 to 92,000 and are related in gene sequence to collagenase. All family members are secreted as zymogens that lose peptides of about 10,000 daltons upon activation. Latency is due to a conserved cysteine that binds to zinc at the active center. Latency is overcome by physical (chaotropic agents), chemical (HOCl, mercurials), and enzymatic (trypsin, plasmin) treatments that separate the cysteine residue from the zinc. Expression of the metalloproteinases is switched on by a variety of agents acting through regulatory elements of the gene, particularly the AP-1 binding site. A family of protein inhibitors of Mr 28,500 or less binds strongly and stoichiometrically in noncovalent fashion to inhibit members of the family. The serum protein alpha 2-macroglobulin and relatives are also strongly inhibitory.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fasebj.5.8.1850705

Matrix metalloproteinases and their inhibitors in connective tissue remodeling.

Werner, Sabine, and Richard Grose. Regulation of Wound Healing by Growth Factors and Cytokines. Physiol Rev 83: 835–870, 2003; 10.1152/physrev.00032.2002.—Cutaneous wound healing is a complex proce...

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Regulation of Wound Healing by Growth Factors and Cytokines

Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn(++)-endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors. The regulation of MMP activity at the transcriptional level and at the extracellular level (precursor activation, inhibition of activated, mature enzymes) is also discussed. A final segment of the review details the current knowledge of the involvement of MMP in specific developmental or pathological conditions, including human periodontal diseases.

Matrix Metalloproteinases: A Review

Deletions or mutations of the retinoblastoma gene, RB1, are common features of many tumors and tumor cell lines. Recently, the RB1 gene product, p105-RB, has been shown to form stable protein/protein complexes with the oncoproteins of two DNA tumor viruses, the adenovirus E1A proteins and the simian virus 40 (SV40) large T antigen. Neither of these viruses is thought to be associated with human cancer, but they can cause tumors in rodents. Binding between the RB anti-oncoprotein and the adenovirus or SV40 oncoprotein can be recapitulated in vitro with coimmunoprecipitation mixing assays. These assays have been used to demonstrate that the E7 oncoprotein of the human papilloma virus type-16 can form similar complexes with p105-RB. Human papilloma virus-16 is found associated with approximately 50 percent of cervical carcinomas. These results suggest that these three DNA viruses may utilize similar mechanisms in transformation and implicate RB binding as a possible step in human papilloma virus-associated carcinogenesis.

https://science.sciencemag.org/content/sci/243/4893/934.full.pdf

The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product

An amazing sequence arrangement at the 5′ ends of adenovirus 2 messenger RNA

X-linked Alport syndrome is a hereditary glomerulonephritis in which progressive loss of kidney function is often accompanied by progressive loss of hearing. Ultrastructural defects in glomerular basement membranes (GBM) of Alport syndrome patients implicate an altered structural protein as the cause of nephritis. The product of COL4A5, the alpha 5(IV) collagen chain, is a specific component of GBM within the kidney, and the gene maps to the same X chromosomal region as does Alport syndrome. Three structural aberrations were found in COL4A5, in intragenic deletion, a Pst I site variant, and an uncharacterized abnormality, which appear to cause nephritis and deafness, with allele-specific severity, in three Alport syndrome kindreds in Utah.

https://science.sciencemag.org/content/sci/248/4960/1224.full.pdf

Identification of mutations in the COL4A5 collagen gene in Alport syndrome.

Complex splicing patterns of RNAs from the early regions of adenovirus-2

Human papillomavirus type 16 and 18 gene expression in cervical neoplasias.

Cyclin E, an essential regulatory subunit of Cdk2 (Dulic et al. 1992; Koff et al. 1992), plays a central role in coordinating both the onset of S phase and centrosome duplication in multicellular eukaryotes (Sherr 1996; Reed 1997). Cyclin E/Cdk2 complexes have two major roles in promoting S phase. First, cyclin E/Cdk2 participates, together with cyclin D/Cdk4, in the control of transcriptional processes that are critical to cell cycle progression. The best understood example is control of the E2F/DP transcription factor via phosphorylation of a family of transcriptional repressors (Rb, p130, and p107) (for review, see Reed 1997; Dyson 1998; Nevins 1998). E2F complexes regulate the S-phase-dependent expression of a number of proteins required for the synthesis of nucleic acids as well as proteins such as Cdc2 and cyclin A that promote subsequent cell cycle transitions. Second, cyclin E/Cdk2 can function in an E2F-independent manner to activate DNA replication. Accumulation of cyclin E is required for S-phase entry, and ectopic cyclin E expression can bypass the requirement for Rb inactivation and E2F activation for S-phase entry (Ohtsubo et al. 1995; Leng et al. 1997; Lukas et al. 1997).

An understanding of the role of cyclin E/Cdk2 in promoting S phase requires knowledge of its essential substrates. Insight into Cdk targets has been advanced by the finding that several Cdk substrates bind tightly to the cyclin subunit. In some cases, this interaction involves a motif in the substrate, the RXL motif, and a conserved pocket in the cyclin box (Zhu et al. 1995; Adams et al. 1996; Russo et al. 1996; Schulman et al. 1998; Brown et al. 1999; Ma et al. 1999). We and others have exploited this property of cyclins to identify relevant cyclin E/Cdk2 substrates with the use of expression cloning (Zhao et al. 1998; Ma et al. 1999). One of these, p220NPAT, interacts with cyclin E/Cdk2 in extracts from tissue culture cells and accelerates S-phase entry when overexpressed (Zhao et al. 1998). Moreover, retroviral insertion into the mouse p220NPAT gene leads to embryonic lethality at the eight-cell stage, indicating an essential role for p220 in cell division or development (Di Fruscio et al. 1997). However, the precise function of p220 and the role of cyclin E/Cdk2 in its action remain unknown.

Emerging data (Zhao et al. 2000, this paper) suggest that p220 is involved in S-phase-specific histone gene transcription. Histones, components of nucleosomes, have to be supplied on demand during DNA replication. This regulation is attributed to both transcriptional and posttranscriptional control mechanisms (Harris et al. 1991; Heintz 1991), mediated in part by the activation of histone gene–specific transcription factors (Oct-1 in the case of the H2B promoter and H1TF2 in the case of the H1 promoter) through an unknown mechanism (Fletcher et al. 1987; Segil et al. 1991). Once generated, histone messages are stabilized and processed preferentially in S phase. Implicated in histone gene transcription are Cajal bodies (CBs; sometimes referred to as coiled bodies). CBs were initially described as small nuclear organelles (Cajal 1903), but their function has remained obscure for the better part of the twentieth century. Recent work has led to the hypothesis that CBs are sites of assembly of transcription and splicing complexes (Gall et al. 1999). The link to histone transcription comes from the finding that a subset of CBs is physically associated with histone gene clusters on chromosomes 1 (1q21) and 6 (6p21) (Frey and Matera 1995) and with histone gene loci in Xenopus lampbrush chromosomes (Abbott et al. 1999). Moreover, CBs also contain a component of the histone mRNA 3′-end processing machinery SLBP1 (Abbott et al. 1999).

Here, we report that p220NPAT is localized to discrete foci that are coincident with a subset of CBs in normal diploid fibroblasts. The number of p220 foci increased from two in Go and G1 cells in association with chromosome 6 to four in S and G2 phases in association with both chromosomes 6 and 1. Foci are lost during mitosis. Consistent with these observations, Zhao et al. (2000) have found that p220 is associated directly with histone gene clusters and that overexpression of p220 can activate histone 2B and histone 4 transcription. We also demonstrate that cyclin E is contained in p220 foci and that p220 within CBs is phosphorylated on Cdk sites in a cell cycle–dependent manner. Moreover, mutation of cyclin E/Cdk2 phosphorylation sites in p220 reduces its ability to activate expression from histone H2B reporter constructs in transiently transfected cells. These data, together with those of Zhao et al. (2000), suggest that cyclin E/Cdk2 functions in conjunction with p220 to coordinate S-phase-dependent histone gene transcription; they also demonstrate a role for CBs in cell cycle–regulated transcriptional control.

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Louise T. Chow

Papers

An amazing sequence arrangement at the 5′ ends of adenovirus 2 messenger RNA

Identification of mutations in the COL4A5 collagen gene in Alport syndrome.

Complex splicing patterns of RNAs from the early regions of adenovirus-2

Human papillomavirus type 16 and 18 gene expression in cervical neoplasias.

Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription.