Androgen-induced proliferative quiescence in prostate cancer cells: The role of AS3 as its mediator

Spo76p is conserved and related to the fungal proteins Pds5p and BIMD and the human AS3 prostate proliferative shutoff-associated protein. Spo76p localizes to mitotic and meiotic chromosomes, except at metaphase(s) and anaphase(s). During meiotic prophase, Spo76p assembles into strong lines in correlation with axial element formation. As inferred from spo76-1 mutant phenotypes, Spo76p is required for sister chromatid cohesiveness, chromosome axis morphogenesis, and chromatin condensation during critical transitions at mitotic prometaphase and meiotic midprophase. Spo76p is also required for meiotic interhomolog recombination, likely at postinitiation stage(s). We propose that a disruptive force coordinately promotes chromosomal axial compaction and destabilization of sister connections and that Spo76p restrains and channels the effects of this force into appropriate morphogenetic mitotic and meiotic outcomes.

In a retrospective review the response of 67 patient with metastatic adenocarcinoma of the prostate to the administration of exogenous testosterone was analyzed. Among 52 patients in whom objective and/or subjective responses were evaluable 45 experienced unfavorable responses. There was prompt regression of most unfavorable responses with testosterone withdrawal. The duration of treatment required to evoke an unfavorable response was related to the clinical status of the patient. Twenty-five per cent of patients with symptomatic metastases who had received no prior treatment, 36 per cent in symptomatic remission after endocrine therapy and 94 per cent with symptomatic relapse after endocrine therapy experienced unfavorable responses within 30 days of treatment. No patient had objective evidence of tumor regression during testosterone therapy but 7 patients, 6 with remission and 1 untreated, experienced symptomatic benefit. We conclude that the response of patients with metastatic prostate cancer to exogenous testosterone is related to the mass and endocrine treatment status, and that exogenous testosterone can stimulate prostatic neoplasms that proliferate in the absence of normal endogenous testosterone levels.

As an extension of our cDNA analysis for deducing the coding sequences of unidentified human genes, we have newly determined the sequences of 100 cDNA clones from a set of size-fractionated human brain cDNA libraries, and predicted the coding sequences of the corresponding genes, named KIAA0611 to KIAA0710. In vitro transcription-coupled translation assay was applied as the first screening to select cDNA clones which produce proteins with apparent molecular mass of 50 kDa and over. One hundred unidentified cDNA clones thus selected were then subjected to sequencing of entire inserts. The average size of the inserts and corresponding open reading frames was 4.9 kb and 2.8 kb (922 amino acid residues), respectively. Computer search of the sequences against the public databases indicated that predicted coding sequences of 87 genes were similar to those of known genes, 62% of which (54 genes) were categorized as proteins related to cell signaling/communication, cell structure/motility and nucleic acid management. The expression profiles in 10 human tissues of all the clones characterized in this study were examined by reverse transcription-coupled polymerase chain reaction and the chromosomal locations of the clones were determined by using human-rodent hybrid panels.