Protein kinase Cα (PKCα) regulates p53 localization and melanoma cell survival downstream of integrin αv in three-dimensional collagen and in vivo.

Protein kinase C α (PKCα) is overexpressed in numerous types of cancer. Importantly, PKCα has been linked to metastasis of malignant melanoma in patients. However, it has been unclear how PKCα may be regulated and how it exerts its role in melanoma.

PRIMA-1Met/APR-246 induces wild-type p53-dependent suppression of malignant melanoma tumor growth in 3D culture and in vivo.

Disseminating malignant melanoma is a lethal disease highly resistant to radio- and chemotherapy. Therefore, the development of new treatment strategies is strongly needed. Tumor suppressor p53-mediated apoptosis is essential for the response to radio- and chemotherapy.

p21-activated kinase 4 phosphorylation of integrin beta5 Ser-759 and Ser-762 regulates cell migration.

Modulation of integrin alphavbeta5 regulates vascular permeability, angiogenesis, and tumor dissemination. In addition, we previously found a role for p21-activated kinase 4 (PAK4) in selective regulation of integrin alphavbeta5-mediated cell motility (Zhang, H., Li, Z.

Anchorage-independent cytokinesis as part of oncogenic transformation?

Cell anchorage to the extracellular matrix (ECM) controls the cell proliferation in all multicellular organisms and the abrogation of this control is an indicator of cellular transformation. In fact, two distinct periods of the cell cycle are subject to anchorage-dependent regulation. Firstly, anchorage exerts an extensive control of the G(1)-phase, a control that we found to be more rigorous than for example the control by growth factors.

Oncogenic H-Ras V12 promotes anchorage-independent cytokinesis in human fibroblasts.

Cell anchorage is required for cell proliferation of untransformed cells, whereas anchorage-independent growth can be induced by oncogenes and is a hallmark of transformation. Whereas anchorage-dependent control of the progression of the G(1) phase of the cell cycle has been extensively studied, it is less clear whether and how anchorage may control other cell cycle phases and whether oncogenes may affect such controls. Here, we found that lack of cell anchorage did not influence progression through the cell cycle S phase, G(2) phase, or most of mitosis of primary human fibroblasts.

Retinoblastoma susceptibility gene product (pRb) and p107 functionally separate the requirements for serum and anchorage in the cell cycle G1-phase.

Growth factors and cell anchorage are both required for cell cycle G(1)-phase progression, but it is unclear whether their function is mediated through the same set of cell cycle components and whether they are both required during the same periods of time. We separately analyzed the requirements of serum and anchorage during G(1)-phase progression and found that human dermal fibroblasts as well as wild type, pRb(-/-), and p107(-/-) mouse embryonic fibroblasts needed serum (growth factors) until mid-G(1)-phase but required cell anchorage until late G(1)-phase to be competent for S-phase entry. Importantly, however, pRb/p107 double-null mouse embryonic fibroblasts lacked serum requirement in mid-G(1)-phase but still required cell anchorage until late G(1)-phase to enter S-phase.