Allelic deletion at 11q23.3-q25 is an early event in cervical neoplasia

Abstract

We have studied the involvement of murine c-Crk, an SH2/SH3 containing adaptor protein, in signaling pathways stimulated by di erent receptor tyrosine kinases. We show here that c-Crk is associated with components of insulin-and PDGF-dependent signaling pathways. Insulin treatment of murine myoblast cells induces the formation of stable complex of endogenous cCrk with insulin receptor substrate-1 (IRS-1) mediated via the SH2 domain of Crk. The ligand dependent physical association of c-Crk with IRS-1 is direct. However IRS-1 is also co-precipitated with c-Crk from quiescent L6 cells. The association of IRS-1 with c-Crk in quiescent cells is probably not direct since Far Western blot analysis did not reveal the binding of neither SH2 domain nor amino-terminal SH3 domain of c-Crk to IRS-1 from unstimulated cells. We also show that PDGF treatment of murine myoblast cells induces association of c-Crk with the PDGF receptor and tyrosine phosphorylation of c-Crk. Overexpression of cCrk enhanced insulin-but not PDGF-induced activation of MAP kinases when compared to parental cell lines. Thus, the formation of the direct IRS-1/Crk complex appears to be crucial for Crk-mediated insulin-induced activation of MAP kinase, whereas Crk is probably involved in other PDGF-induced responses. These data provide support to the hypothesis that insulin and PDGF employ di erent mechanisms for activation of MAP kinase cascade.

Deletion of 11q23 and Cyclin D1 Overexpression Are Frequent Aberrations in Parathyroid Adenomas

“…Importantly, all three cases that had 11q23 deletion by CGH and FISH and that were further investigated with FISH to determine the MEN1 allele copy number, had both MEN1 alleles located at 11q13 present, suggesting the possibility that 11q23 might contain an important suppressor gene that is distinct from MEN1. 35 This hypothesis is supported by the frequent deletion of 11q22-q24 in several human cancers, such as ovarian and colorectal carcinoma, and mantle cell lymphoma. 36 -39 One candidate tumor suppressor gene located at 11q23 is PPP2R1B that encodes the ␤ isoform of the A subunit of the serine/threonine protein phosphatase 2A (PP2A), and deletion of PPP2R1B may lead to colon or lung cancer.…”

Biotinyl-Tyramide-Based In Situ Hybridization Signal Patterns Distinguish Human Papillomavirus Type and Grade of Cervical Intraepithelial Neoplasia

“…This concept is also supported by the demonstration that CIN II/III lesions associated with high-risk types have a monoclonal origin (25). Secondary clonal expansions may subsequently give rise to punctatediffuse signal type heterogeneity and other forms of intralesional heterogeneity, such as allelic imbalance (26). A high prevalence of integration in CIN II/III lesions is consistent with the development of invasive capacity, depending not on integration per se (which may of itself support cell proliferation; 4) but on the (stochastic) acquisition of key genetic defects (7) subsequent to loss of E6/E7 regulation.…”

Telomere attrition predominantly occurs in precursor lesions during in vivo carcinogenic process of the uterine cervix

“…Such continuous re-organization of cellular genome eventually creates novel molecular events essential for fully malignant transformation. Although we were unable to sort out those individual cells carrying very weak telomere signals to perform comparative genomic hybridization due to technical difficulties, based on previous observations showing a high frequency of chromosomal aberrations in CINs (Southern et al, 1997;Aubele et al, 1998;Evans et al, 1998;Giannoudis et al, 2000;Umayahara et al, 2002;Heselmeyer-Haddad et al, 2003;Pihan et al, 2003), it is rational to attribute genomic alterations to substantial telomere loss in those precursor lesions of the uterine cervix. Taken together, we suggest that telomere shortening and the resultant genetic instability may be key events in the formative stages of cervical cancers, which is consistent with those seen in animal and in vitro human tumorigenic models.…”