The Growth and Tumor Suppressors NORE1A and RASSF1A Are Targets for Calpain-Mediated Proteolysis

Кузнецов, С. Л.; Khokhlatchev, Andrei

doi:10.1371/journal.pone.0003997

Cited by 13 publications

(17 citation statements)

References 31 publications

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“…Inhibits cell growth, arrests cell cycle [58,62] Involved in actin cytoskeleton organization [148] Induces apoptosis [58,62,145] Suppresses transcriptional activity of NFjB [181] Inhibits MST2 activity [93] K-Ras [62] PAR4 [64] MST1 [66,177] MST2 [177] Yes [67] growth retardation, systematic haematopoietic anomalies, defects in osteoclast and osteoblast differentiation 3 12q14. 1 …”

Section: Rassf1amentioning

confidence: 99%

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RASSF tumor suppressor gene family: Biological functions and regulation

et al. 2014

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a b s t r a c tGenetic changes through allelic loss and nucleic acid or protein modifications are the main contributors to loss of function of tumor suppressor proteins. In particular, epigenetic silencing of genes by promoter hypermethylation is associated with increased tumor severity and poor survival. The RASSF (Ras association domain family) family of proteins consists of 10 members, many of which are tumor suppressor proteins that undergo loss of expression through promoter methylation in numerous types of cancers such as leukemia, melanoma, breast, prostate, neck, lung, brain, colorectal and kidney cancers. In addition to their tumor suppressor function, RASSF proteins act as scaffolding agents in microtubule stability, regulate mitotic cell division, modulate apoptosis, control cell migration and cell adhesion, and modulate NFjB activity and the duration of inflammation. The ubiquitous functions of these proteins highlight their importance in numerous physiological pathways. In this review, we will focus on the biological roles of the RASSF family members and their regulation.

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Section: Rassf1amentioning

confidence: 99%

“…Alternative to epigenetic silencing, RASSF5A can be downregulated through proteolysis catalyzed by calpain proteins, offering a means for tumor cells to flourish and escape growth inhibition [148]. RASSF5C promoter methylation is a rare event, possibly because its expression is limited to lymphoid tissue.…”

Section: Thementioning

confidence: 99%

RASSF tumor suppressor gene family: Biological functions and regulation

et al. 2014

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“…Additionally, NORE1A is often down regulated in tumors by epigenetic inactivation via promoter hypermethylation and can undergo loss of heterozygosity in a rare form of kidney cancer [14,137]. At a protein level, NORE1A can also be down regulated in tumor cells by calpains and by ubiquitination [138,139]. In liver cancer, more malignant primary tumor samples have an inverse correlation with NORE1A expression, whereas normal liver tissue expresses NORE1A [140].…”

Section: The Nore1a Tumor Suppressor (Rassf5)mentioning

confidence: 99%

The discovery of a novel, Ras-mediated NORE1A/PMLIV tumor suppressor complex.

Sharpe¹

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“…can also be regulated at the mRNA [138] and protein levels [139]. Protein array analysis from breast tissue tumor samples would be necessary to determine more accurate NORE1A/BRCA1 expression levels.…”

Section: Nore1a Appears To Be Acting As a Direct Communication Link Bmentioning

confidence: 99%

The Ras effector NORE1A forms a tumor suppressor complex with BRCA1.

Nelson

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Ras proteins function as molecular signaling switches that can stimulate multiple mitogenic pathways in response to extracellular signaling. Oncogenic activation of Ras by structural mutation is a highly transforming event in ~1/3 of human cancers. However, aberrant Ras activation can also promote oncogene-induced senescence. This Rasinduced irreversible growth arrest is a physiological process that acts as a barrier to malignancy. The mechanisms by which Ras drives senescence and how this process is bypassed during Ras-driven transformation remains poorly understood.Although mutations in the RAS gene are extremely rare in human breast cancer, the Ras signaling pathway is constitutively activated in roughly half of all primary breast tumors. This is largely due to aberrant activation of upstream regulators of Ras, like the EGFR family member Her2 and inactivation of negative Ras regulators, such as NF1.NORE1A (RASSF5) is a direct Ras effector that acts as a tumor suppressor by promoting apoptosis and senescence. Expression of NORE1A is frequently lost in primary breast tumors and breast cancer cell lines, though its mechanism of action in breast cancer pathogenesis remains unclear. vi BRCA1 is a tumor suppressor that plays a key role in DNA DSB repair. Loss of BRCA1 is associated with hereditary breast and ovarian cancer, and is also thought to play a role in sporadic breast cancer. Recently, BRCA1 was shown to play a role in both Her2 and Ras senescence, but the mechanism underlying the communication between Her2/Ras and BRCA1 was not identified.I have discovered that NORE1A forms an endogenous, Her2/Ras-regulated complex with BRCA1. I show that dual suppression of NORE1A and BRCA1 has a synergistic effect on transformation. Furthermore, I show that NORE1A loss suppresses the BRCA1-mediated senescence effect. Finally, I show that NORE1A and BRCA1 synergize to modulate DNA repair. Thus, I identify a novel tumor suppressor complex that connects Her2/Ras senescence signaling to BRCA1 in breast cancer. GAPs stabilize the catalytic machinery of Ras, enhancing its intrinsic ability to hydrolyze GTP into GDP and returning Ras to its inactive conformation.5 In addition to mitogenic signaling, activated Ras can also drive apoptosis and senescence.Ras signaling through Raf can promote p53-mediated apoptosis, and has also been implicated in senescence induction via p21 and p16. Ras-mediated activation of RASSF1A leads to apoptosis via activation of pro-apoptotic BAX proteins, or by activation of the pro-apoptotic Hippo pathway via phosphorylation of the MST kinases.RASSF1A has also been reported to drive senescence via p53-independent regulation of p21. Ras-mediated activation of NORE1A can promote p53-dependent upregulation of p21 to drive cell cycle arrest or senescence.12 Ras growth inhibitory effectorsThe RASSF familyThere are ten RASSF family members (along with various isoforms), which are now split into two groups: the "classical" members (RASSF1-6), which contain an RA domain and a SARAH domain at their C-term...

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The Growth and Tumor Suppressors NORE1A and RASSF1A Are Targets for Calpain-Mediated Proteolysis

Cited by 13 publications

References 31 publications

RASSF tumor suppressor gene family: Biological functions and regulation

RASSF tumor suppressor gene family: Biological functions and regulation

The discovery of a novel, Ras-mediated NORE1A/PMLIV tumor suppressor complex.

The Ras effector NORE1A forms a tumor suppressor complex with BRCA1.

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