RGD Reference Report - The membrane mucin Muc4 inhibits apoptosis induced by multiple insults via ErbB2-dependent and ErbB2-independent mechanisms. - Rat Genome Database

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The membrane mucin Muc4 inhibits apoptosis induced by multiple insults via ErbB2-dependent and ErbB2-independent mechanisms.

Authors: Workman, HC  Sweeney, C  Carraway KL, 3RD 
Citation: Workman HC, etal., Cancer Res. 2009 Apr 1;69(7):2845-52. doi: 10.1158/0008-5472.CAN-08-2089. Epub 2009 Mar 17.
RGD ID: 7349401
Pubmed: PMID:19293191   (View Abstract at PubMed)
PMCID: PMC2745945   (View Article at PubMed Central)
DOI: DOI:10.1158/0008-5472.CAN-08-2089   (Journal Full-text)

The aberrant expression of membrane mucins such as Muc1 and Muc4 by tumor cells has been shown to engage signaling pathways that promote cellular properties associated with tumor progression. Our previous studies have shown that Muc4 interacts with and potentiates signaling by the ErbB2 (HER2) receptor tyrosine kinase through an epidermal growth factor-like domain in its extracellular region. Here, we show that expression of Muc4 in human A375 melanoma cells and MCF7 breast cancer cells confers resistance to apoptosis induced by a variety of stimuli, including chemotherapeutic agents, the absence of serum factors, and the loss of cellular adhesion. Mapping experiments revealed that the O-glycosylation and cytosolic domains of Muc4 are dispensable for its antiapoptotic activity, and are also dispensable for the potentiation of signaling by ErbB2. Knockdown of endogenous Muc4 in JIMT-1 breast cancer cells sensitizes cells to apoptotic stimuli, and this can be rescued by Muc4 forms lacking the O-glycosylation or cytosolic domains. Surprisingly, however, the molecular mechanisms underlying Muc4 antiapoptotic activity vary among cell lines. Although Muc4 in JIMT-1 cells engages ErbB2 to promote cell survival, its antiapoptotic mechanism in MCF7 and A375 cells seems to be independent of ErbB2. However, Muc4 expression in all cell lines culminates in the phosphorylation and inactivation of the proapoptotic protein Bad and the elevation of the prosurvival protein Bcl-xL. Our observations suggest that tumor cells can exploit the versatile antiapoptotic activities of Muc4 to acquire resistance to therapeutic agents, and augment cell survival after the loss of adhesion and microenvironment-derived survival factors.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Muc4Ratnegative regulation of apoptotic process  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Muc4  (mucin 4, cell surface associated)


Additional Information