Loss of DBC2 Expression is an Early and Progressive Event in the Development of Lung Adenocarcinoma

Wang, Dong; Li, Meng; Shen, Hongchang; Du, Jiajun

doi:10.7314/apjcp.2012.13.5.2021

Cited by 9 publications

(6 citation statements)

References 19 publications

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“…Subsequent studies further found that DBC2 expression was suppressed in approximately 60% of breast cancers, 50 to 70% of lung cancers, and 75% of bladder cancers [4], [14], [15]. Loss of DBC2 expression in bladder and breast cancer was associated with aberrant methylation of the gene's promoter [14], [16], [17].…”

Section: Introductionmentioning

confidence: 99%

Hsp90-Dependent Assembly of the DBC2/RhoBTB2-Cullin3 E3-Ligase Complex

et al. 2014

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The expression of the wild-type tumor-suppressor gene DBC2 (Deleted-in-Breast Cancer 2, a.k.a RhoBTB2) is suppressed in many cancers, in addition to breast cancer. In a screen for Cdc37-associated proteins, DBC2 was identified to be a potential client protein of the 90 kDa heat shock protein (Hsp90) chaperone machine. Pull down assays of ectopically expressed DBC2 confirmed that DBC2 associated with Hsp90 and its co-chaperone components in reticulocyte lysate and MCF7 cells. Similar to other atypical Rho GTPases, DBC2 was found to have retained the capacity to bind GTP. The ability of DBC2 to bind GTP was modulated by the Hsp90 ATPase cycle, as demonstrated through the use of the Hsp90 chemical inhibitors, geldanamycin and molybdate. The binding of full length DBC2 to GTP was suppressed in the presence of geldanamycin, while it was enhanced in the presence of molybdate. Furthermore, assembly of DBC2-Cullin3-COP9 E3 ligase complexes was Hsp90-dependent. The data suggest a new paradigm for Hsp90-modulated assembly of a Cul3/DBC2 E3 ubiquitin ligase complex that may extend to other E3 ligase complexes.

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Section: Introductionmentioning

confidence: 99%

Hsp90-Dependent Assembly of the DBC2/RhoBTB2-Cullin3 E3-Ligase Complex

et al. 2014

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“…RhoBTB2, for example, was reported to be homozygously deleted in a large percentage of breast cancer tumors (Hamaguchi et al 2002;Mao et al 2009). Downregulation of RhoBTB2 was further observed in lung, bladder, bone and gastric cancer (Cho et al 2009;Shi et al 2008;Dong et al 2012;Jin et al 2013). Obtained in breast cancer cells, evidence suggests that RhoBTB2 exerts a tumor-suppressive function by inhibiting cancer cell proliferation, migration and invasiveness (Ling et al 2014;Mao et al 2011).…”

Section: Rhobtb Lkb1 (Stk11) Hippo Pathway Ubiquitinationmentioning

confidence: 92%

RhoBTB Proteins Regulate the Hippo Pathway by Antagonizing Ubiquitination of LKB1

Nguyen

Ralbovska

Kugler

2020

G3 Genes|Genomes|Genetics

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The Hippo pathway regulates growth and apoptosis. We identify RhoBTB proteins as novel regulators of Hippo signaling. RhoBTB depletion in the Drosophila wing disc epithelium cooperated with Yki to drive hyperplasia into neoplasia. Depletion of RhoBTB2 caused elevated YAP activity in human cells. RhoBTB2 deficiency resulted in increased colony formation in assays for anchorage-independent growth. We provide evidence that RhoBTBs acts on Hippo signaling through regulation of the kinase LKB1. LKB1 protein levels were reduced upon RhoBTB2 depletion, which correlated with increased LKB1 ubiquitination. Restoring LKB1 levels rescued loss of RhoBTB in Drosophila. Our results suggest that RhoBTB-dependent LKB1 regulation may contribute to its tumor-suppressive function.

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“…Consistent with roles as tumor suppressors, expression of all three RHOBTB genes has been found reduced or extinguished in a variety of tumor types. Expression of RHOBTB2 , the first member of the family to be proposed as a candidate tumor suppressor gene, has been found decreased in breast [ 6 , 24 , 25 ], lung [ 26 ], bladder [ 27 , 28 ], and stomach [ 29 ] cancers, in osteosarcomas [ 30 ], as well as in cell lines derived from breast, lung [ 6 ], and bladder [ 27 ] tumors, and HNSCCs (head and neck squamous cell carcinomas) [ 31 ]. Very often the degree of expression correlates with the primary location, grading, staging, or other features of the tumor.…”

Section: Rhobtbs As Tumor Suppressorsmentioning

confidence: 99%

Atypical Rho GTPases of the RhoBTB Subfamily: Roles in Vesicle Trafficking and Tumorigenesis

Rivero

2016

Cells

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RhoBTB proteins constitute a subfamily of atypical Rho GTPases represented in mammals by RhoBTB1, RhoBTB2, and RhoBTB3. Their characteristic feature is a carboxyl terminal extension that harbors two BTB domains capable of assembling cullin 3-dependent ubiquitin ligase complexes. The expression of all three RHOBTB genes has been found reduced or abolished in a variety of tumors. They are considered tumor suppressor genes and recent studies have strengthened their implication in tumorigenesis through regulation of the cell cycle and apoptosis. RhoBTB3 is also involved in retrograde transport from endosomes to the Golgi apparatus. One aspect that makes RhoBTB proteins atypical among the Rho GTPases is their proposed mechanism of activation. No specific guanine nucleotide exchange factors or GTPase activating proteins are known. Instead, RhoBTB might be activated through interaction with other proteins that relieve their auto-inhibited conformation and inactivated through auto-ubiquitination and destruction in the proteasome. In this review we discuss our current knowledge on the molecular mechanisms of action of RhoBTB proteins and the implications for tumorigenesis and other pathologic conditions.

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Loss of DBC2 Expression is an Early and Progressive Event in the Development of Lung Adenocarcinoma

Cited by 9 publications

References 19 publications

Hsp90-Dependent Assembly of the DBC2/RhoBTB2-Cullin3 E3-Ligase Complex

Hsp90-Dependent Assembly of the DBC2/RhoBTB2-Cullin3 E3-Ligase Complex

RhoBTB Proteins Regulate the Hippo Pathway by Antagonizing Ubiquitination of LKB1

Atypical Rho GTPases of the RhoBTB Subfamily: Roles in Vesicle Trafficking and Tumorigenesis

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