Substituting Threonine 187 with Alanine in p27Kip1 Prevents Pituitary Tumorigenesis by Two-Hit Loss of Rb1 and Enhances Humoral Immunity in Old Age

Zhao, Hongling; Bauzon, Frederick; Bi, Enguang; Yu, Jinlong; Fu, Hao; Lu, Zhonglei; Cui, Jinhua; Jeon, Hyungjun; Zang, Xingxing; Ye, B. Hilda; Zhu, Liang

doi:10.1074/jbc.m114.625350

Cited by 12 publications

(12 citation statements)

References 42 publications

(54 reference statements)

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“…Skp2 has a growing list of substrates in addition to p27; p27T187A KI can test the contribution of lacking p27 ubiquitination by SCF Skp2/Cks1 to the effects of Skp2 KO. In Rb1 deficient pituitary tumorigenesis, p27T187A KI largely phenocopied Skp2 KO to block this tumorigenesis (12, 15). On the other hand, p27T187A KI did not inhibit Kras G12D/+ induced lung tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…pRb inhibits Skp2 via at least three mechanisms (described in the previous section); pRb loss may thereby greatly enhance Skp2 activity, leading to greatly enhanced p27 ubiquitination by SCF Skp2/Cks1 in Rb1 deficient pituitary melanotroph tumorigenesis. In this context, p27 protein degradation became dependent on Thr187 phosphorylation; p27T187A KI therefore can inhibit Rb1 deficient pituitary tumorigenesis (12, 15). …”

Section: Discussionmentioning

confidence: 99%

“…However, when p27 KO accelerated lung tumorigenesis in Kras G12D/+ mice, p27T187A KI did not have a protective effect (10), suggesting that p27 ubiquitination by SCF Skp2/Cks1 is dispensable for p27 degradation in lung tumorigenesis by Kras G12D . On the other hand, p27 KO accelerated pituitary melanotroph tumorigenesis in Rb1 +/− mice (11) and p27T187A KI blocked it (12). Thus, the role of SCF Skp2/Cks1 in mediating p27 degradation can be highly critical in promoting tumorigenesis but only in specific contexts.…”

Section: Introductionmentioning

confidence: 99%

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p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer

Zhao

Bauzon

et al. 2016

Oncogene

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SCFSkp2/Cks1 ubiquitinates Thr187-phosphorylated p27 for degradation. Over-expression of Skp2 coupled with under-expression of p27 are frequent characteristics of cancer cells. When the role of SCFSkp2/Cks1 mediated p27 ubiquitination in cancer was specifically tested by p27 Thr187-to-Ala knockin (p27T187A KI), it was found dispensable for KrasG12D induced lung tumorigenesis but essential for Rb1 deficient pituitary tumorigenesis. Here we identify pRb and p53 doubly deficient (DKO) prostate tumorigenesis as a context in which p27 ubiquitination by SCFSkp2/Cks1 is required for p27 down-regulation. p27 protein accumulated in prostate when p27T187A KI mice underwent DKO prostate tumorigenesis. p27T187A KI or Skp2 knockdown (KD) induced similar degrees of p27 protein accumulation in DKO prostate cells, and Skp2 KD did not further increase p27 protein in DKO prostate cells that contained p27T187A KI (AADKO prostate cells). p27T187A KI activated an E2F1-p73-apoptosis axis in DKO prostate tumorigenesis, slowed disease progression, and significantly extended survival. Querying co-occurrence relationships among RB1, TP53, PTEN, NKX3-1, and MYC in TCGA of prostate cancer identified co-inactivation of RB1 and TP53 as the only statistically significant co-occurrences in metastatic castration resistant prostate cancer (mCRPC). Together, our study identifies Skp2/Cks1 pocket inhibitors as potential therapeutics for mCRPC. Procedures for establishing mCRPC organoid cultures from contemporary patients were recently established. An Skp2/Cks1 pocket inhibitor preferentially collapsed DKO prostate tumor organoids over AADKO organoids, which spontaneously disintegrated over time when DKO prostate tumor organoids grew larger, setting the stage to translate mouse model findings to precision medicine in the clinic on the organoid platform.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer

Zhao

Bauzon

et al. 2016

Oncogene

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“…Zhu and colleagues Gordon et al 2013;Zhao et al 2013) have shown that inactivation of Skp2 can suppress proliferation of p53-and pRB-deficient cells in part through an up-regulation of p27 (Zhao et al 2015) and the activation of E2F1-mediated apoptosis (Lu et al 2014). This genetic interaction is effective at suppressing tumorigenesis in mouse models but has yet to be applied to human tumors.…”

Section: The Translation Of Rb Researchmentioning

confidence: 99%

RB1: a prototype tumor suppressor and an enigma

2016

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The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined. RB1 mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature of RB1 mutations, and its frequency of inactivation, RB1 is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients?

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“…As positive controls, we used salivary gland for DKC1, tonsil for CDK2P-Thr160, kidney for RPS13, and placenta for CDKN1B, CDKN1BP-Thr187 and Cyclin-E1, as established by the Human Protein Atlas (www.pro teinatlas.org). The antibody for CDK2P-Thr160 was chosen to allow evaluation of activated CDK2 [28] and the antibody for CDKN1BP-Thr187 was chosen because this phosphorylation is required for P27 recruitment to ubiquitin ligases [29]. For each studied antibody, the sample was assigned into 2 categories according to the staining.…”

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

P27/CDKN1B Translational Regulators in Pituitary Tumorigenesis

et al. 2016

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In pituitary tumors, P27(CDKN1B) is underexpressed. We aimed to clarify whether translational regulation underlies this phenomenon. This study evaluated the expression of /, its targets (, ) and translational regulators (, ,, ) and screened for variants in sporadic pituitary adenomas. Samples were obtained during transsphenoidal surgery from 48 patients with pituitary adenomas: 10 ACTH-, 17 GH-secreting, and 21 nonfunctioning (NFPA). The control group comprised 7 normal pituitaries (NP) obtained during autopsies. Gene expression was assessed by RT-PCR and protein expression by immunohistochemistry. The 15 exons of were sequenced. P27 protein underexpression was observed in all adenomas subtypes (p=0.001). mRNA (p=0.01) overexpression, but not protein, was observed in NFPA. No differential gene expression among groups was observed in regulators (p=0.23) and (p=0.34). The expression of and was similar among tumors and NP. Frequent variants (SNPs) were found in exon 14 and in the 3'-UTR in similar frequency to NCBI-dsSNP databases. We also observed rare variants in 11% of the studied tumor samples, indicating a high prevalence in pituitary adenomas, however, in silico studies failed to indicate deleterious effects. The high frequency of variants may influence, in some extent, pituitary tumors development, without clear role in its tumorigenesis. Our data reinforce the P27 underexpression in pituitary adenomas and provide further evidence of the post-translational machinery involvement, although this phenomenon cannot be explained either by mis-expression of P27 translational regulators - ,, , - or directly by mutations.

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Substituting Threonine 187 with Alanine in p27Kip1 Prevents Pituitary Tumorigenesis by Two-Hit Loss of Rb1 and Enhances Humoral Immunity in Old Age

Abstract: Background: p27T187A knockin mice facilitate studying p27Kip1 protein in physiology. Results: p27T187A knockin prevented pituitary tumorigenesis in Rb1 ϩ/Ϫ mice and enhanced humoral response to immuniza-

Cited by 12 publications

References 42 publications

p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer

p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer

RB1: a prototype tumor suppressor and an enigma

P27/CDKN1B Translational Regulators in Pituitary Tumorigenesis

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