The BCR/ABL oncogenic tyrosine kinase activates phosphatidylinositol 3‐kinase (PI‐3k) by a mechanism that requires binding of BCR/ABL to p85, the regulatory subunit of PI‐3k, and an intact BCR/ABL SH2 domain. SH2 domain BCR/ABL mutants deficient in PI‐3k activation failed to stimulate Akt kinase, a recently identified PI‐3k downstream effector with oncogenic potential, but did activate p21 RAS and p70 S6 kinase. The PI‐3k/Akt pathway is essential for BCR/ABL leukemogenesis as indicated by experiments demonstrating that wortmannin, a PI‐3k specific inhibitor at low concentrations, suppressed BCR/ABL‐dependent colony formation of murine marrow cells, and that a kinase‐deficient Akt mutant with dominant‐negative activity inhibited BCR/ABL‐dependent transformation of murine bone marrow cells in vitro and suppressed leukemia development in SCID mice. In complementation assays using mouse marrow progenitor cells, the ability of transformation‐defective SH2 domain BCR/ABL mutants to induce growth factor‐independent colony formation and leukemia in SCID mice was markedly enhanced by expression of constitutively active Akt. In retrovirally infected mouse marrow cells, the BCR/ABL mutant lacking the SH2 domain was unable to upregulate the expression of c‐Myc and Bcl‐2; in contrast, expression of a constitutively active Akt mutant induced Bcl‐2 and c‐Myc expression, and stimulated the transcription activation function of c‐Myc. Together, these data demonstrate the requirement for the BCR/ABL SH2 domain in PI‐3k activation and document the essential role of the PI‐3k/Akt pathway in BCR/ABL leukemogenesis.

Melanoma is a cancer that exhibits one of the most aggressive and heterogeneous features. The incidence rate escalates. A high number of clones harboring various mutations contribute to an exceptional level of intratumor heterogeneity of melanoma. It also refers to metastases which may originate from different subclones of primary lesion. Such component of the neoplasm biology is termed intertumor and intratumor heterogeneity. These levels of tumor heterogeneity hinder accurate diagnosis and effective treatment. The increasing number of research on the topic reflects the need for understanding limitation or failure of contemporary therapies. Majority of analyses concentrate on mutations in cancer-related genes. Novel high-throughput techniques reveal even higher degree of variations within a lesion. Consolidation of theories and researches indicates new routes for treatment options such as targets for immunotherapy. The demand for personalized approach in melanoma treatment requires extensive knowledge on intratumor and intertumor heterogeneity on the level of genome, transcriptome/proteome, and epigenome. Thus, achievements in exploration of melanoma variety are described in details. Particularly, the issue of tumor heterogeneity or homogeneity given BRAF mutations is discussed.

The prognosis for patients with mantle cell lymphoma (MCL) is poor, and at present there is no truly effective therapy. Gene translocation-mediated constitutive expression of cyclin D1 seems to play the key role in the pathogenesis of MCL. Here we report that although 3 of 4 MCL cell lines expressed the recently identified, highly oncogenic cyclin D1b isoform, as well as the canonical cyclin D1a, 8 MCL patient samples expressed only the cyclin D1a protein despite expressing detectable cyclin D1b mRNA. Cell lines and tissue samples displayed constitutive activation of the cyclin D1 signaling cascade, as evidenced by strong expression of CDK4, Rb phosphorylation, and cyclin D1/CDK4 coassociation. All MCL cell lines and tissues examined displayed nondetectable to diminished expression of the cyclin D1 inhibitor p16. Novel small molecule CDK4/CDK6 inhibitor PD0332991 profoundly suppressed—at low nanomolar concentrations—Rb phosphorylation, proliferation, and cell cycle progression at the G0/G1 phase of MCL cells. These findings provide evidence that MCL should be very sensitive to targeted therapy aimed at functional inhibition of the cyclin D1/CDK4 complex.

MiRNAs are short non-coding RNAs that regulate gene expression post-transcriptionally contributing to the development of different diseases including cancer. The miR-200 family consists of five members, miR-200a, miR-200b, miR-200c, miR-141, and miR-429. Their expression is dysregulated in cancer tissue and their level is altered in the body fluids of cancer patients. Moreover, the levels of miR-200 family members correlate with clinical parameters such as cancer patients’ survival which makes them potentially useful as diagnostic and prognostic biomarkers. MiRNAs can act as either oncomiRs or tumor suppressor miRNAs depending on the target genes and their role in the regulation of key oncogenic signaling pathways. In most types of cancer, the miR-200 family acts as tumor suppressor miRNA and regulates all features of cancer. In this review, we summarized the expression pattern of the miR-200 family in different types of cancer and their potential utility as biomarkers. Moreover, we comprehensively described the role of miR-200 family members in the regulation of all hallmarks of cancer proposed by Hanahan and Weinberg with the focus on the epithelial-mesenchymal transition, invasiveness, and metastasis of tumor cells.

Phosphoinositides have a pivotal role as precursors to important second messengers and asbona fide signaling and scaffold targeting molecules. Phosphatidylinositol 4-kinases (PtdIns 4-kinases or PI4Ks) are at the apex of the phosphoinsitide cascade. Sequence analysis revealed that mammalian cells contain two type II PtdIns 4-kinase isoforms, now termed PI4KIIα and PI4KIIβ. PI4KIIα was cloned first. It is tightly membrane-associated and behaves as an integral membrane protein. In this study, we cloned PI4KIIβ and compared the two isoforms by monitoring the distribution of endogenous and overexpressed proteins, their modes of association with membranes, their response to growth factor stimulation or Rac-GTP activation, and their kinetic properties. We find that the two kinases have different properties. PI4KIIβ is primarily cytosolic, and it associates peripherally with plasma membranes, endoplasmic reticulum, and the Golgi. In contrast, PI4KIIα is primarily Golgi-associated. Platelet-derived growth factor promotes PI4KIIβ recruitment to membrane ruffles. This effect is potentially mediated through Rac; overexpression of the constitutively active RacV12 induces membrane ruffling, increases PI4KIIβ translocation to the plasma membrane, and stimulates its activity. The dominant-negative RacN17 blocks plasma membrane association and inhibits activity. RacV12 does not boost the catalytic activity of PI4KIIα further, probably because it is constitutively membrane-bound and already activated. Membrane recruitment is an important mechanism for PI4KIIβ activation, because microsome-bound PI4KIIβ is 16 times more active than cytosolic PI4KIIβ. Membrane-associated PI4KIIβ is as active as membrane-associated PI4KIIα and has essentially identical kinetic properties. We conclude that PI4KIIα and PI4KIIβ may have partially overlapping, but not identical, functions. PI4KIIβ is activated strongly by membrane association to stimulate phosphatidylinositol 4,5-bisphosphate synthesis at the plasma membrane. These findings provide new insight into how phosphoinositide cascades are propagated in cells.