Activation of NF-kappaB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-kappaB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-kappaB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-kappaB pathway in the pathogenesis of multiple myeloma.

The retinoblastoma protein, pRB, and the closely related proteins p107 and p130 are important regulators of the mammalian cell cycle. Biochemical and genetic studies have demonstrated overlapping as well as distinct functions for the three proteins in cell cycle control and mouse development. However, the role of the pRB family as a whole in the regulation of cell proliferation, cell death, or cell differentiation is not known. We generated embryonic stem (

Defects in neural tube formation are among the most common malformations leading to infant mortality. Although numerous genetic loci appear to contribute to the defects observed in humans and in animal model systems, few of the genes involved have been characterized at the molecular level. Mice lacking the p53 tumour suppressor gene are predisposed to tumours, but the viability of these animals indicates that p53 function is not essential for embryonic development. Here, we demonstrate that a fraction of p53-deficient embryos in fact do not develop normally. These animals display defects in neural tube closure resulting in an overgrowth of neural tissue in the region of the mid-brain, a condition known as exencephaly.

The pl30 protein shares extensive sequence similarity with pRB, the product of the retinoblastoma gene, and is a major E2F-associated protein in quiescent cells. To investigate its biological function, we have mutated pl30 via gene targeting in the mouse. Homozygous mutation of pl30 had little discernible effect on development or on the growth of mouse embryo fibroblasts in culture. Much of the E2F activity that normally associates with pl30 in serum-starved mouse embryo fibroblasts associated instead with the highly related pl07 protein. To determine whether pl30 and pl07 have overlapping biological roles, we produced mice having simultaneous inactivation of the pl30 and pl07 genes. Such mice exhibited deregulated chondrocyte growth, defective endochondral bone development, shortened limbs, and neonatal lethality. These findings indicate that pl30 and pl07 play an important role in limb development through their abilities to control chondrocyte proliferation. Thus, in certain settings pl07 and pl30 perform growth-regulatory functions that are not fulfilled by pRB.