The p16^INK4a tumor suppressor inhibits cyclin-dependent kinases (CDK4 and CDK6). Here we report the isolation of a novel gene, SEI-1, whose product (p34^SEI-1) appears to antagonize the function of p16^INK4a. Addition of p34^SEI-1 to cyclin D1–CDK4 renders the complex resistant to inhibition by p16^INK4a. Expression of SEI-1 is rapidly induced on addition of serum to quiescent fibroblasts, and ectopic expression of p34^SEI-1 enables fibroblasts to proliferate even in low serum concentrations. p34^SEI-1 seems to act as a growth factor sensor and may facilitate the formation and activation of cyclin D–CDK complexes in the face of inhibitory levels of INK4 proteins.

After i.p. infection of mice with the intracellular bacterium Mycobacterium bovis bacillus Calmette-Guérin, macrophages recovered from the peritoneal cavity display classical signs of immune activation. We have identified a member of the serine protease inhibitor (serpin) family which is highly induced in macrophages during bacillus Calmette-Guérin infection. Serpin 2a (spi2a) expression is also induced in macrophages in vivo during infection with Salmonella typhimurium and Listeria monocytogenes, and in vitro by a variety of bacteria and bacterial products. The cytokine IFN-γ also induces spi2a expression in macrophages, and this induction is synergistic with bacterial products. We also demonstrate here that a ubiquitin homolog, IFN-stimulated gene of 15-kDa (ISG15), is strongly induced during in vitro and in vivo activation of macrophages and that it conjugates to spi2a in activated macrophages. The ISG15-spi2a conjugates were identified by tandem mass spectrometry and contained spi2a conjugated to either one or two molecules of ISG15. Whereas spi2a was induced by either bacterial products or IFN-γ, ISG15 was induced only by bacterial products. Although many protein targets have been described for ubiquitin conjugation, spi2a is the first ISG15-modified protein to be reported. Macrophage activation is accompanied by the activation of a variety of proteases. It is of interest that a member of the serine protease inhibitor family is concomitantly induced and modified by a ubiquitin-like protein.

In contrast to the developed nations, invasive cervical cancer (ICC) is the most common womens malignancy in Kenya and many other locations in sub-Saharan Africa. However, studies on survival from this disease in this area of the world are severely restricted by lack of patient follow-up. We now report a prospective cohort study of ICC in Kenyan women analysing factors affecting tumour response and overall survival in patients undergoing radiotherapy. Between 2008 and 2010, 355 patients with histologically confirmed ICC were recruited at the Departments of Gynaecology and Radiotherapy at Kenyatta National Hospital (KNH). Structured questionnaires were completed recording socio-demographics, tumour response and overall survival following treatment with combinations of external beam radiation (EBRT), brachytherapy and adjuvant chemotherapy. Of the 355 patients, 42% (146) were lost to follow-up while 18% (64) died during the two year period. 80.5% of patients presented with advanced stage IIB disease or above, with only 6.7% of patients receiving optimal combined EBRT, brachytherapy and adjuvant chemotherapy. Kaplan Meier survival curves projected two year survival at <20%. Cervical cancer is preventable yet poverty, poor education, lack of cancer awareness coupled with an absence of regular screening programs, late patient presentation, sub-optimal diagnosis and treatments are major factors contributing to the alarmingly low survival rate of cervical cancer patients in Kenya. It is concluded that simple cost-effective changes in clinical practice could be introduced which would have a marked impact on patient survival in this setting.

Using a murine transplantation model, we have investigated the function of the HPV16 E6 and E7 proteins in the development of radiation resistance in advanced cervical carcinoma. Constitutive high‐level expression of the HPV16 E6 oncogene in HPV negative human C33A cervical carcinoma cells was shown to induce rapid onset and radiation resistance in transplanted tumors when compared with tumors derived from E7 or vector transfected cells. The radiation‐ resistant, E6 tumor phenotype was not due solely to increased hypoxia, because all E6 tumors were shown to be uniformly hypoxic, and artificial induction of hypoxia, in E7 and control tumors, failed to produce the same degree of radiobiological resistance. Differential screening of a 1.2‐k human cancer cDNA array indicated that E6 tumors had up‐regulated expression of the DNA nucleotide excision repair gene excision repair cross‐complementation enzyme 1 (ERCC1). High‐level expression of ERCC1 mRNA and protein was found to be restricted to radiation‐resistant E6 tumors. In vitro maintenance of E6 and control vector‐expressing cells under anoxic conditions showed that ERCC1 expression was induced preferentially in E6‐ expressing cells. These data indicate that the HPV16 E6 protein may influence the response to therapy of cervical carcinoma by inappropriate activation of DNA repair mechanisms.