Phosphorylation and Activation of Androgen Receptor by Aurora-A

Shu, Shaokun; Liu, Qiyuan; Coppola, Domenico; Cheng, Jin Q.

doi:10.1074/jbc.m110.121129

Cited by 32 publications

(22 citation statements)

References 45 publications

(56 reference statements)

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“…Intriguingly, in the AVPC, AURKA nuclear expression correlated with AR expression. Indeed, the interactome of AURKA is large(37) and includes cell cycle and transcriptional regulators such as AR(38), Tp53(39), MYC(40), and BRCA1(41). In turn, Tp53 mutants increase AURKA expression and cooperate with AURKA in the induction of genomic instability(42) (also a likely feature of the AVPC suggested by the high rate of CNA observed) and in the regulation of DNA damage repair(43).…”

Section: Discussionmentioning

confidence: 99%

Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers

Aparicio

Шен

Tapia

et al. 2016

Clinical Cancer Research

223

210

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Purpose Morphologically heterogeneous prostate cancers (PC) that behave clinically like small cell PC (SCPC) share their chemotherapy responsiveness. We asked whether these clinically defined, morphologically diverse, ‘aggressive variant PC’ (AVPC) also share molecular features with SCPC. Experimental Design 59 PC samples from 40 clinical trial participants meeting AVPC criteria, and 8 patient-tumor derived xenografts (PDX) from 6 of them, were stained for markers aberrantly expressed in SCPC. DNA from 36 and 8 PDX was analyzed by Oncoscan® for copy number gains (CNG) and losses (CNL). We used the AVPC PDX to expand observations and referenced publicly available data sets to arrive at a candidate molecular signature for the AVPC. Results Irrespective of morphology, Ki67 and Tp53 stained ≥ 10% cells in 80% and 41% of samples respectively. RB1 stained <10% cells in 61% of samples and AR in 36%. MYC (surrogate for 8q) CNG and RB1 CNL showed in 54% of 44 samples each and PTEN CNL in 48%. All but 1 of 8 PDX bore Tp53 missense mutations. RB1 CNL was the strongest discriminator between unselected castration resistant PC (CRPC) and the AVPC. Combined alterations in RB1, Tp53 and/or PTEN were more frequent in the AVPC than in unselected CRPC and in The Cancer Genome Atlas samples. Conclusions Clinically defined AVPC share molecular features with SCPC and are characterized by combined alterations in RB1, Tp53 and/or PTEN.

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Section: Discussionmentioning

confidence: 99%

Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers

Aparicio

Шен

Tapia

et al. 2016

Clinical Cancer Research

223

210

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“…95). There are many examples of serine/threonine and tyrosine kinases implicated in AR phosphorylation and amongst the most interesting are Aurora kinase A (Aurora-A), 96 cyclin-dependent kinase 1 (Cdk1), 97,98 PIM1 kinase, 99 Src and Ack1; 100–102 all of these are targets of small molecule inhibitors in clinical development.…”

Section: Mechanisms Of Maintained Ar Activity In Crpcmentioning

confidence: 99%

Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects

et al. 2014

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Androgen receptor (AR) signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer (CRPC) has changed dramatically in the last several years. Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and to paradigm shift in the treatment. Accumulating evidence showed that prostate cancers develop adaptive mechanisms for maintaining AR signaling to allow for survival and further evolution. The aim of this review is to summarize molecular mechanisms of castration resistance and provide an update in the development of novel agents and strategies to more effectively target the AR signaling pathway.

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“…In vitro kinase assays showed that the AR can be phosphorylated by the Serine/Threonine kinase Aurora-A (Shu et al 2010). Sequence analysis predicted that the N-terminal T282 and S293 were two potential Aurora-A phosphorylation sites.…”

Section: T282 and S293 Phosphorylationmentioning

confidence: 99%

Androgen receptor phosphorylation: biological context and functional consequences

Koryakina¹,

Ta²,

Gioeli³

2014

Endocrine-Related Cancer

121

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The androgen receptor (AR) is a ligand-regulated transcription factor that belongs to the family of nuclear receptors. In addition to regulation by steroid, the AR is also regulated by post-translational modifications generated by signal transduction pathways. Thus, the AR functions not only as transcription factor, but also as a node that integrates multiple extracellular signals. The importance of the AR in disease cannot be understated as it plays a role in many diseases ranging from complete androgen insensitivity syndrome to spinal bulbar muscular atrophy to prostate and breast cancer. In the case of prostate cancer, dependence on AR signaling has been exploited for therapeutic intervention for decades. However, the effectiveness of these therapies is limited in advanced disease due to restoration of AR signaling. Fully understanding the molecular mechanisms of AR action will enable the development of future therapeutics for the wide range of AR dependent diseases. The AR is subject to regulation by a number of kinases through post-translational modifications on serine, threonine and tyrosine residues. Here we review the AR phosphorylation sites, the kinases responsible for these phosphorylations, as well as the biological context and the functional consequences of these phosphorylations. Finally, what is known about the state of AR phosphorylation in clinical samples is discussed.

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Phosphorylation and Activation of Androgen Receptor by Aurora-A

Cited by 32 publications

References 45 publications

Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers

Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers

Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects

Androgen receptor phosphorylation: biological context and functional consequences

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