Identification of Nuclear Import Mechanisms for the Neuronal Cdk5 Activator

Fu, Xinrong; Choi, Yuk-Kwan; Qu, Dianbo; Yu, Yan; Cheung, Nam Sang; Qi, Robert Z.

doi:10.1074/jbc.m512663200

Cited by 55 publications

(46 citation statements)

References 43 publications

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“…S3B). In addition, p35 protein was also reported to translocate into nuclei via a direct interaction with importins without associating with Cdk5 (43). This finding suggests that p35 may enter the nucleus by itself and activate nuclear Cdk5 and subsequently result in Ser-81 phosphorylation of nuclear AR.…”

Section: Discussionmentioning

confidence: 71%

Regulation of Androgen Receptor and Prostate Cancer Growth by Cyclin-dependent Kinase 5

Hsu

Chen

Chiang

et al. 2011

Journal of Biological Chemistry

114

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Prostate cancer is the most frequently diagnosed male malignancy. The normal prostate development and prostate cancer progression are mediated by androgen receptor (AR). Recently, the roles of cyclin-dependent kinase 5 (Cdk5) and its activator, p35, in cancer biology are explored one after another. We have previously demonstrated that Cdk5 may regulate proliferation of thyroid cancer cells. In addition, we also identify that Cdk5 overactivation can be triggered by drug treatments and leads to apoptosis of prostate cancer cells. The aim of this study is to investigate how Cdk5 regulates AR activation and growth of prostate cancer cells. At first, the data show that Cdk5 enables phosphorylation of AR at Ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of AR proteins. The Cdk5-dependent AR stabilization causes accumulation of AR proteins and subsequent activation. Besides, the positive regulations of Cdk5-AR on cell growth are also determined in vitro and in vivo. S81A mutant of AR diminishes its interaction with Cdk5, reduces its nuclear localization, fails to stabilize its protein level, and therefore, decreases prostate cancer cell proliferation. Prostate carcinoma specimens collected from 177 AR-positive patients indicate the significant correlations between the protein levels of AR and Cdk5 or p35. These findings demonstrate that Cdk5 is an important modulator of AR and contributes to prostate cancer growth. Therefore, Cdk5-p35 may be suggested as diagnostic and therapeutic targets for prostate cancer in the near future.Prostate cancer is a commonly diagnosed malignancy in men, and androgen plays an important role in its early development (1). Androgen deprivation has been considered as a common therapy for androgen-dependent prostate cancer. However, the existing cancer cells eventually become hormone-refractory, and the following therapy usually gets into scrapes. The androgen receptor (AR), 2 which belongs to the steroid receptor family and plays pivotal roles in the development of the prostate gland and the pathogenic progression of prostate cancer. High levels of AR expression along with its target genes have been reported in hormone-refractory prostate cancer cells, suggesting that AR signaling is activated regardless of the levels of serum androgen (2). A study analyzing consensus sequences of phosphorylation indicates that AR contains more than 40 predicted phosphorylation sites (3). Ser-81 of the AR N terminus is the most intensely phosphorylated site in response to androgen binding (4). The latest report reveals the relevance of Ser-81 phosphorylation and AR promoter selectivity as well as cell growth (5). Our recent work also shows the increase of Ser-81 phosphorylation of AR in the androgen-independent LNCaP sub-line (6). Fu et al. (7) proposed that the phosphorylation consensus sequence (SPRT) of cyclin-dependent kinase 5 (Cdk5) corresponds with the sequence around AR Ser-81. Although AR was reported as substrates for Cdk9 (5) as well as Cdk1 (8), whi...

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Section: Discussionmentioning

confidence: 71%

Regulation of Androgen Receptor and Prostate Cancer Growth by Cyclin-dependent Kinase 5

Hsu

Chen

Chiang

et al. 2011

Journal of Biological Chemistry

114

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“…Cdk5 binding to either p35 or its p25 breakdown product occludes the Cdh1 ubiquitination site and thus protects Cdk5 from ubiquitin-dependent proteolysis, maintaining its presence in the cell. The importance of p35 binding is demonstrated by the finding that the ⌬P35 mutant, which is unable to bind with Cdk5 (18), is unable to block the interaction between Cdk5 and Cdh1 and thus unable to block the ubiquitination of Cdk5. In support of this model, the truncation constructs (Fig.…”

Section: That Apcmentioning

confidence: 99%

Cdk5 Levels Oscillate during the Neuronal Cell Cycle

Zhang

Zhou

et al. 2012

Journal of Biological Chemistry

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Background:Cdk5 is an atypical Cdk that inhibits the cell cycle in post-mitotic neurons. Results: APC-Cdh1 mediates the degradation of Cdk5 during S phase of the cell cycle. Conclusion: Maintenance of the proper levels and nuclear location of Cdk5 act to suppress the cell cycle in neuronal cells. Significance: Subcellular localization of Cdk5 and p35 may play roles in the pathogenesis of Alzheimer disease.

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“…This family of transporters controls general and varied processes in all eukaryotic organisms. In humans, Imp5 regulates, for example, neuronal differentiation and degeneration by the import of p35 protein (Fu et al, 2006), chromosome structure by the import of core histones (Baake et al, 2001), and specific DNA recombination processes through RAG-2 binding (Ross et al, 2003). In yeast, Kap121p/Pse1p is an essential protein that regulates multiple pathways such as the phosphate stress response via Pho4p import (Kaffman et al, 1998), the oxidative stress response via Yap1 (Isoyama et al, 2001), membrane biogenesis by Pdr1 (Delahodde et al, 2001), and both mating response and pseudohyphal transition mediated by Ste12 (Leslie et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

KapI, a non-essential member of the Pse1p/Imp5 karyopherin family, controls colonial and asexual development in Aspergillus nidulans

Etxebeste

Markina-Iñarrairaegui

Garzia

et al. 2009

Microbiology

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Asexual development in the filamentous fungus Aspergillus nidulans is governed by the timely expression and cellular localization of multiple transcription factors. Hence, factors mediating import and export across the nuclear pore complexes (karyopherins) are expected to play a key role in coordinating the developmental programme. Here we characterize KapI, a putative homologue of the Saccharomyces cerevisiae Kap121/Pse1p karyopherin. KapI is a non-essential importin-b-like protein located in the nucleus during vegetative growth and conidiophore development. The DkapI phenotype is aconidial with many aerial hyphae. This phenotype can be suppressed under abiotic stress. In this regard, it resembles that of the null allele of the bZIP transcription factor FlbB. However a DflbB; DkapI double mutant exhibited an additive phenotype with totally impaired conidiation, unresponsive to abiotic stress. In contrast to DflbB, the null kapI mutant is not a fluffy-low-bristle expression mutant. Taken together the findings indicate that KapI is required during asexual development, mediating the nuclear transport of factors acting in a different pathway(s) from those involving the upstream developmental activators.

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Identification of Nuclear Import Mechanisms for the Neuronal Cdk5 Activator

Cited by 55 publications

References 43 publications

Regulation of Androgen Receptor and Prostate Cancer Growth by Cyclin-dependent Kinase 5

Regulation of Androgen Receptor and Prostate Cancer Growth by Cyclin-dependent Kinase 5

Cdk5 Levels Oscillate during the Neuronal Cell Cycle

KapI, a non-essential member of the Pse1p/Imp5 karyopherin family, controls colonial and asexual development in Aspergillus nidulans

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