SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia

Pearson, Helen; Pérez–Mancera, Pedro A.; Dow, Lukas E.; Ryan, Andrew; Tennstedt, Pierre; Bogani, Debora; Elsum, Imogen; Greenfield, Andy; Tuveson, David A.; Simon, Ronald; Humbert, Patrick O.

doi:10.1172/jci58509

Cited by 158 publications

(206 citation statements)

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“…(17,48) HTLV-2 Tax2 protein has also been shown to play a crucial role in the immortalization ability of the virus. (17,18,43,49) We established peripheral T-cells immortalized by either Tax1 or Tax2, and the expression of MAGI-1 in these cells was determined. Our data indicated that while (15) were used as IL-2-dependent cells (lane 2-9).…”

Section: Resultsmentioning

confidence: 99%

“…Tax1 through the PBM has been shown to interact with cellular PDZ domain containing proteins, some of which are implicated in tumor suppression, (31)(32)(33) for instance deficiency of Scribble in mice induced prostate cancer through activating MAP kinase pathway. (49) Nevertheless, it remains unclear whether these PDZ proteins explain any of the Tax1 PBM functions or other cellular PDZ protein(s) play(s) a major role in Tax1 functions. The present study identifies MAGI-1 as a novel Tax1 interacting partner and found that Tax1 aberrantly sequesters MAGI-1 into Tax1 containing complexes and translocates it from the detergent-soluble to the detergent-insoluble cellular fraction (Figs 2,3).…”

Section: Discussionmentioning

confidence: 99%

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Human T‐cell leukemia virus type 1 Tax protein interacts with and mislocalizes the PDZ domain protein MAGI‐1

et al. 2013

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Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL). HTLV-1 encodes the oncoprotein Tax1, which is essential for immortalization of human T-cells and persistent HTLV-1 infection in vivo. Tax1 has a PDZ binding motif (PBM) at its C-terminus. This motif is crucial for the transforming activity of Tax1 to a T-cell line and persistent HTLV-1 infection. Tax1 through the PBM interacts with PDZ domain proteins such as Dlg1 and Scribble, but it has not been determined yet, which cellular PDZ proteins mediate the functions of Tax1 PBM. Here we demonstrate that Tax1 interacts with the PDZ domain protein MAGI-1 in a PBM-dependent manner, and the interaction mislocalizes MAGI-1 from the detergent-soluble to the detergent-insoluble cellular fraction in 293T cells and in HTLV-1-infected T-cells. In addition, Tax1-transformation of a T-cell line from interleukin (IL)-2-dependent to IL-2-independent growth selects cells with irreversibly reduced expression of MAGI-1 at mRNA level. These findings imply that Tax1, like other viral oncoproteins, targets MAGI-1 as a mechanism to suppress its anti-tumor functions in HTLV-1-infected cells to contribute to the transforming activity of T-cells and persistent HTLV-1 infection. (Cancer Sci 2013; 104: 313-320) H uman T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL).(1,2) Among several non-structural genes encoded by HTLV-1, Tax1 is a crucial regulator of viral life cycle as a potent transcriptional activator for its own transcription. (3)(4)(5) In addition, Tax1 is a key player involved in T-cell immortalization, transformation, persistent infection, inflammation, and leukemogenesis. (6)(7)(8)(9)(10)(11) All these pleitropic functions of Tax1 are believed to be directed by a wide spectrum of interactions with cellular factors. For instance, numerous PDZ domain containing cellular proteins have been shown to complex with Tax1 through the PDZ binding motif (PBM) located at its C-terminus. (12,13) We have previously shown that the PBM plays a key role in Tax1 mediated activities. The motif was critically involved in Tax1-induced transformation of a rat fibroblast cell line and a mouse T-cell line. (14,15) Moreover, an HTLV-1DPBM virus with a deletion of the Tax1 PBM in HTLV-1, failed to establish persistent infection in rabbits as measured by lack of antibody response against HTLV-1 and the absence of HTLV-1 proviruses. (16) Human T-cell leukemia virus type 2 (HTLV-2) is closely related to HTLV-1, but it is unable to cause any malignancy. (17,18) One notable difference between the two is the lack of PBM in Tax2, and thus Tax1 PBM is proposed to be one of the major determinants of HTLV-1 pathogenesis. (14,19) Intriguingly, PBMs have been identified in other viral oncoproteins such as the E4-ORF1 protein of human adenovirus type 9 and the E6 proteins of high-risk human papilloma viruses (HPV), (20)(21)(22) suggesting that the oncogenic ability of these viruses may depend in part on interactions invo...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human T‐cell leukemia virus type 1 Tax protein interacts with and mislocalizes the PDZ domain protein MAGI‐1

et al. 2013

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“…In Drosophila, SCRIB regulates apical-basal polarity and morphogenesis in epithelial cells (Bilder and Perrimon, 2000;Legouis et al, 2003), and spindle polarity in dividing neuroblasts (Albertson and Doe, 2003). In mammals, SCRIB regulates apical-basal polarity in epithelial cells (Qin et al, 2005;Godde et al, 2014;Pearson et al, 2011), front-back polarity in migrating astrocytes, T cells, fibroblasts and epithelial cells (Dow et al, 2007;Ludford-Menting et al, 2005;Nola et al, 2008;Osmani et al, 2006) and planar cell polarity of the stereociliary bundle in the inner ear cochlea (Montcouquiol et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Scribble is required for pregnancy-induced alveologenesis in the adult mammary gland

Baker

BeGora

Yeung

et al. 2016

Journal of Cell Science

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The cell polarity protein scribble (SCRIB) is a crucial regulator of polarization, cell migration and tumorigenesis. Whereas SCRIB is known to regulate early stages of mouse mammary gland development, its function in the adult gland is not known. Using an inducible RNA interference (RNAi) mouse model for downregulating SCRIB expression, we report an unexpected role for SCRIB as a positive regulator of cell proliferation during pregnancy-associated mammary alveologenesis. SCRIB was required in the epithelial cell compartment of the mammary gland. Lack of SCRIB attenuated prolactin-induced activation of the JAK2-STAT5 signaling pathway. In addition, loss of SCRIB resulted in the downregulation of prolactin receptor (PRLR) at cell surface and its accumulation in intracellular structures that express markers of the Golgi complex and the recycling endosome. Unlike its role in virgin gland as a negative regulator cell proliferation, SCRIB is a positive regulator of mammary epithelial cell proliferation during pregnancy.

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“…Evidence suggests the conservation of a tumor suppressive role in mammals (Martin-Belmonte and Perez-Moreno, 2011;Pearson et al, 2011) as well as an important role in influencing the Hippo pathway (Cordenonsi et al, 2011). Currently there is thus much interest in understanding the fundamental activity of the Scrib module.…”

Section: Introductionmentioning

confidence: 99%

The Scribble module regulates retromer-dependent endocytic trafficking during epithelial polarization

et al. 2014

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Scribble (Scrib) module proteins are major regulators of cell polarity, but how they influence membrane traffic is not known. Endocytosis is also a key regulator of polarity through roles that remain unclear. Here we link Scrib to a specific arm of the endocytic trafficking system. Drosophila mutants that block AP-2-dependent endocytosis share many phenotypes with Scrib module mutants, but Scrib module mutants show intact internalization and endolysosomal transport. However, defective traffic of retromer pathway cargo is seen, and retromer components show strong genetic interactions with the Scrib module. The Scrib module is required for proper retromer localization to endosomes and promotes appropriate cargo sorting into the retromer pathway via both aPKC-dependent and -independent mechanisms. We propose that the Scrib module regulates epithelial polarity by influencing endocytic itineraries of Crumbs and other retromer-dependent cargo.

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SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia

Cited by 158 publications

References 55 publications

Human T‐cell leukemia virus type 1 Tax protein interacts with and mislocalizes the PDZ domain protein MAGI‐1

Human T‐cell leukemia virus type 1 Tax protein interacts with and mislocalizes the PDZ domain protein MAGI‐1

Scribble is required for pregnancy-induced alveologenesis in the adult mammary gland

The Scribble module regulates retromer-dependent endocytic trafficking during epithelial polarization

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