Sos-mediated cross activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis
نویسندگان
چکیده
Mammalian cells contain three closely related ras genes, H-ras, K-ras and N-ras. Although in a given tumour type, oncogenic mutations are selectively observed in only one of the ras genes, the acquisition of the transformed phenotype has been shown to require the contribution of the normal products of the other ras genes. Here we demonstrate that oncogenic K-Ras promotes the activation of wild-type H- and N-Ras. This activation is mediated by oncogenic K-Ras-dependent allosteric stimulation of Sos and confers a growth advantage to oncogenic K-Ras harbouring cancer cells. These findings underscore the complementary functions of oncogenic and wild-type Ras in tumour cells and identify a potential new targeting strategy for Ras-driven tumours.
منابع مشابه
Reduced HRASG12V-Driven Tumorigenesis of Cell Lines Expressing KRASC118S
In many different human cancers, one of the HRAS, NRAS, or KRAS genes in the RAS family of small GTPases acquires an oncogenic mutation that renders the encoded protein constitutively GTP-bound and thereby active, which is well established to promote tumorigenesis. In addition to oncogenic mutations, accumulating evidence suggests that the wild-type isoforms may also be activated and contribute...
متن کاملB-Raf is dispensable for K-Ras-mediated oncogenesis in human cancer cells.
Oncogenic mutations in B-Raf and Kirsten-Ras (K-Ras) are mutually exclusive during human cancer pathogenesis. In an effort to study the biological basis of this epistasis, gene targeting was used to create isogenic sets of human cancer cells differing only in presence or absence of endogenous oncogenic K-Ras or wild-type B-Raf. Whereas cells lacking the K-Ras oncogene were unable to efficiently...
متن کامل[Frontiers in Bioscience 9, 3486-3509, September 1, 2004] 3486 DEVELOPMENT OF NEW ANTI-CANCER PEPTIDES FROM CONFORMATIONAL ENERGY ANALYSIS OF THE ONCOGENIC ras-P21 PROTEIN AND ITS COMPLEXES WITH TARGET PROTEINS
1. Abstract 2. Introduction 2.1. Mutated proteins can induce malignant transformation 2.2. Mutant ras-p21 Protein Is a Major Cause of Cancer 2.3. ras-induced signal transduction pathways 2.4. Direct interactions between ras-p21 and target proteins depends largely on two of its domains 2.5. How amino acid substitutions in ras-p21 can induce it to become oncogenic 3. Methods 3.1. Computational me...
متن کاملInhibition of RAS-mediated transformation and tumorigenesis by targeting the downstream E3 ubiquitin ligase seven in absentia homologue.
Constitutively active RAS small GTPases promote the genesis of human cancers. An important goal in cancer biology is to identify means of countervailing activated RAS signaling to reverse malignant transformation. Oncogenic K-RAS mutations are found in virtually all pancreatic adenocarcinomas, making the RAS pathway an ideal target for therapeutic intervention. How to best contravene hyperactiv...
متن کاملApproach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange.
Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active upstream receptor tyrosine kinases results in the deregulation of cellular signals governing growth and survival in ∼30% of all human cancers. However, the discovery of potent inhibitors of Ras has been difficult to achieve. Here, we report the identification of small molecules that bind to a unique pocke...
متن کامل