Elucidation of mechanisms regulating cell cycle progression is of fundamental importance for cell and cancer biology. Although several genes and signaling pathways are implicated in G1–S regulation, less is known regarding the mechanisms controlling cell cycle progression through G2 and M phases. We report that extracellular signal–regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinases, is activated at G2–M and required for timely mitotic entry. Stimulation of ERK5 activated nuclear factor κB (NFκB) through ribosomal S6 kinase 2 (RSK2)-mediated phosphorylation and degradation of IκB. Furthermore, selective inhibition of NFκB at G2–M phases substantially delayed mitotic entry and inhibited transcription of G2–M–specific genes, including cyclin B1, cyclin B2, Plk-1, and cdc25B. Moreover, inhibition of NFκB at G2–M diminished mitosis induced by constitutive activation of ERK5, providing a direct link between ERK5, NFκB, and regulation of G2–M progression. We conclude that a novel ERK5–NFκB signaling pathway plays a key role in regulation of the G2–M progression.
In this cohort of men with prostate cancer, short CAG repeat length on the androgen receptor gene was associated with African-American race and possibly with higher stage but not with other clinical or pathologic findings.
The action of androgens in the development and growth of prostate carcinomas is well documented. The androgen receptor (AR) facilitates androgen-induced regulation of genes involved in cellular proliferation and differentiation. Since the early 1940s androgen ablation has been the cornerstone of treatment for metastatic prostate cancer. Although initially highly effective, hormonal therapy is not curative, and resistant disease will ultimately prevail. Mutations that alter AR conformation, function, and regulation may provide a selective growth advantage for subpopulations of cells within the tumor that are then able to proliferate in an androgen-deprived environment. Clinically, these mutations are important because they may lead to the growth of androgen-independent tumors and progression to a refractory state. Further characterization of AR mutations will lead to a more thorough understanding of their role in the development of prostate carcinomas. This information, in addition to discovering which genes are regulated by the AR, can aid in the future development of more effective pharmacotherapy for prostate cancer.
The androgen receptor plays a major role in the development and function of normal and malignant prostate cells. Due to the relationship of the androgen receptor and prostatic growth, it has been proposed that polymorphisms within the androgen receptor may play a role in an individual’s susceptibility to developing prostate cancer. An inverse relationship has been established between a highly polymorphic trinucleotide repeat located in the first exon of the androgen receptor and the transactivaton function of the receptor. Serum samples were collected from 131 patients with histologically confirmed adenocarcinoma of the prostate, DNA was isolated, and the polymorphic CAG repeat was amplified by PCR and sequenced. The CAG repeat lengths were then compared with age at diagnosis, age at time of study, baseline log10 PSA, Gleason score, time from diagnosis to initiation of hormonal therapy, time to progression after androgen ablation, and overall survival time. No correlation was found between CAG length and time to progression or overall survival time, but a significant correlation was found between Gleason score and CAG length suggesting that shorter CAG lengths may predict a higher histological grade of prostate cancer.
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